JP6153513B2 - Radiolabeled compounds as radiotracers for quantitative imaging of phosphodiesterase (PDE10A) in mammals and uses thereof - Google Patents

Description

  The present invention relates generally to novel radiolabeled compounds and their use as radioactive tracers for quantitative imaging of phosphodiesterase 10A (PDE10A) in mammals.

(Background of the Invention)
Non-invasive nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of various living subjects including laboratory animals, normal humans and patients. These techniques rely on the use of sophisticated image processing equipment that can detect radiation emitted from radioactive tracers administered to such living subjects. The obtained information can be reconstructed to obtain a planar tomographic image that reveals the distribution of the radioactive tracer as a function of time. By using a well-designed radioactive tracer, it is possible to obtain an image containing the structure, function and most importantly physiological and biochemical information of the object. Much of this information cannot be obtained by other means. Radiotracers used in these studies are defined in vivo behavior that allows measurement of specific information regarding the physiology or biochemistry of a subject or the effects of various diseases or drugs on the physiology or biochemistry of a subject. Designed to show. Currently, radioactive tracers can be used to obtain useful information on things like cardiac function, myocardial blood flow, pulmonary blood perfusion, liver function, cerebral blood flow, tumor imaging, local cerebral glucose and oxygen metabolism. it can.

The compound can be labeled with a positron or gamma-ray radionuclide. For imaging, the most commonly used positron emitting (PET) nuclides are ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, all of which are manufactured with an accelerator, 20 minutes, 110 minutes, respectively. Has a half-life of 2 minutes and 10 minutes. These nuclides have very short half-lives, so their use is limited because they can only be used at or very close to their research sites with accelerators. Several radioactive tracers that emit gamma radiation are available and can be used in virtually any hospital in the United States and most hospitals around the world. The most widely used of these are ^99m Tc, ²⁰¹ Tl and ¹²³ I.

  In the last 20 years, one of the most active areas of nuclear medicine research has been the development of receptor-imaging radioactive tracers. These tracers bind to selective and neuronal receptors with high affinity and specificity. Successful examples include radioactive tracers for imaging the following receptor systems, estrogens, muscarinic agonists, serotonin, dopamine, opiates, neuropeptide-Y, cannabinoid-1 and neurokinin-1.

Schizophrenia is a serious neuropsychiatric syndrome that usually affects late adolescence or early adulthood. Positive or psychotic symptoms, including delusions and hallucinations, are the most prominent symptoms of disability. These appear seizures and usually cause the first hospitalization in early adulthood. Chronic aspects of the disorder include social withdrawal, flat emotion, and negative symptoms such as loss of pleasure and pervasive cognitive impairment. The latter is closely associated with weak functional outcomes and long-term prognosis (Green et al., Schizophr. Res. (2004) 72: 41-51; Harvey et al., J. Clin. Psychiatry (2004) 65: 361-372). While dopamine D ₂ receptor antagonists are effective against positive symptoms, these drugs are not effective against negative symptoms and cognitive symptoms of schizophrenia, except for excessive dopaminergic effects in the cortex Systems (eg, reduced NMDA receptor function and GABA function) may also be implicated in the pathophysiology of schizophrenia (Ross et al., Neuron (2006) 52: 139 -153). D ₂ antagonists (typical antipsychotics) are known to cause extrapyramidal side effects (EPS) and hyperprolactinemia by excessive D ₂ receptor antagonism in the brain (Michael et al. al., Expert Opin. Pharmacother. (2006) 7: 1005-1016). Although atypical antipsychotics such as olanzapine and risperidone have a lower incidence of EPS than typical antipsychotics, these drugs remain hyperprolactinemia, hyperglycemia, weight gain, diabetes, and multiple neurotransmissions It has severe metabolic side effects such as abnormal lipid profile due to interaction with substance receptors (Michael et al., Expert Opin. Pharmacother. (2006) 7: 1005-1016). Thus, new drugs with strong efficacy against negative and cognitive symptoms as well as positive symptoms and a better safety profile would deserve therapeutic value.

  Recently, it has been postulated that inhibition of cyclic nucleotide phosphodiesterase (PDE) will provide a new therapeutic approach to the treatment of schizophrenia (Frank et al., Nat. Rev. Drug Disc. (2000) 5 : 660-670; Frank et al., Curr. Opin. Investig. Drugs (2000) 8: 54-59). The PDE superfamily of enzymes is encoded by 21 genes and subdivided into 11 different families by structural and functional properties (Andrew et al., Pharmacol. Rev. (2006) 58: 488-520). These enzymes metabolically inactivate ubiquitous intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE selectively catalyzes the hydrolysis of 3'-ester bonds to form inactive 5'-monophosphate. Based on substrate specificity, the PDE family is further divided into three groups: i) cAMP-PDEs (PDE4, PDE7, PDE8), ii) cGMP-PDEs (PDE5, PDE6 and PDE9), and iii) two. Dual-substrate PDEs (PDE1, PDE2, PDE3, PDE10 and PDE11).

PDE10 has the most localized expression distribution in the known PDE family. PDE10 mRNA is highly expressed only in the brain and testis (Fujimoto et al., J. Biol. Chem. (1999) 274: 18438-18445; Loughney et al., Gene (1999) 234: 109-117; Soderling et al., Proc. Natl. Acad. Sci. USA (1999) 96: 7071-7076). PDE10 protein is also highly expressed in the brain in several mammalian species and shows a localized expression distribution in the peripheral system. (Thomas et al., Brain Research (2003) 985: 113-126). In the mammalian brain, PDE10 mRNA and protein show very high expression in medium spiny neurons (MSNs) in the striatum (Thomas et al., Brain Research (2003) 985: 113). -126; Xieet al., Neuroscience (2006) 139: 597-607; Timothy et al., J. Histochem. Cyto. (2006) 54: 1205-1213), by affecting both cAMP and cGMP signaling cascades, Controls the output of the striatum (Judith et al., Neuropharmacology (2006) 51: 374-385; Judith et al., Neuropharmacology (2006) 51: 386-396). MSN is mainly classified into two routes. Direct expressing D ₁ dopamine receptors - Indirect expressing (striatonigral) path and D ₂ dopamine receptors (striatum - globus pallidus) is a passage (Graybiel et al, Trends Neurosci ( .. 1990) 13: 244-254; Graybiel et al., Curr. Biol. (2000) 10: 509-511). These paths have the opposite effect on the output of the striatum. Since PDE10 is expressing in both pathways, elevation of cyclic nucleotide striatal occurring as PDE10 inhibitors and the results, together with the D ₁ acts to minimize the load of the extrapyramidal side effects, standard of psychosis It would have potentially a D ₂ antagonism is a therapeutic. This specific expression distribution and function in the brain indicates that PDE10 is an important new target for the treatment of neurological and psychiatric disorders, especially psychiatric disorders such as schizophrenia.

  PET (positron emission tomography) radiotracers and imaging techniques can provide a powerful method for clinical evaluation and dose selection of PDE10A inhibitors. Accordingly, the present invention relates to radiolabeled PDE10A inhibitors, both for in vitro and in vivo imaging and diagnostics for exploratory purposes, and radiolabeled PDE10A inhibitors and non-radiolabeled PDE10A Useful for competitive studies with inhibitors.

  An object of the present invention is to provide a novel radiolabeled compound useful as a radiotracer for quantitatively imaging PDE10A in mammals.

  The present inventors have intensively studied to solve the above-mentioned problems, and a radioactive tracer in which the compounds represented by the formulas (I) and (I ′) described below quantitatively image PDE10A in mammals. As found useful. Further studies by the present inventors based on these findings have led to the completion of the present invention.

That is, the present invention
[1] Formula (I):

[Where,
Ring A is
(1) benzene,
(2) pyrazole,
(3) thiazole,
(4) piperidine, and (5) is selected from the group consisting tetrahydropyridine, the ring A, halogen, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, substituted Optionally substituted C _7-14 aralkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, and optionally substituted cyclic group (provided that Expression

(Wherein p is 1 to 4), except for a cyclic group represented by the above), may be substituted with 1 to 4 substituents selected from the group consisting of:
R ¹ is radiolabeled optionally substituted C _1-4 alkoxy;
R ² and R ³ are each a substituent;
m is 0-2;
n is 0-5. ]
(Wherein 1- (2-fluorophenyl) -5- [ ¹¹ C] methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one,
1- [4- (3,5-dimethyl-isoxazol-4-yl) -2-fluorophenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine -4 (1H) -On and
1- (2-fluoro-4- (morpholin-4-yl) phenyl) ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) - pyridazine -4 (IH) - On except for)
Or a salt thereof (hereinafter sometimes referred to as Compound (I)).
[2] The compound represented by the formula (I) is represented by the formula (I ′):

[Where,
Ring A ′ is
(1) benzene,
_1-4 substituents selected from the group consisting of (2) piperidine, and (3) tetrahydropyridine, wherein the ring A ′ is selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy. Optionally substituted with a group;
Ring B represents an optionally substituted cyclic group (however, an optionally substituted formula

(Wherein p is 1 to 4). ]
The compound or its salt as described in [1] which is a compound represented by these.
[3] Ring B is
(1) C _3-12 cycloalkyl which may be substituted,
(2) an optionally substituted dihydropyranyl,
(3) optionally substituted tetrahydropyranyl,
(4) optionally substituted azetidinyl,
(5) optionally substituted pyrrolidinyl,
(6) optionally substituted piperidinyl,
(7) optionally substituted imidazolyl,
(8) optionally substituted isoxazolyl,
(9) optionally substituted pyrazolyl,
(10) optionally substituted dihydropyrazolyl,
(11) optionally substituted pyridyl,
(12) optionally substituted pyrrolyl,
(13) an optionally substituted dihydropyrrolyl,
(14) optionally substituted phenyl,
(15) optionally substituted morpholinyl,
(16) an optionally substituted thiazolyl,
(17) optionally substituted oxazolidinyl,
(18) optionally substituted imidazolidinyl,
(19) The compound or a salt thereof according to [2], selected from the group consisting of optionally substituted oxaazabicyclooctyl and (20) optionally substituted oxazepanyl.
[4] The compound or a salt thereof according to [1], wherein R ¹ is optionally substituted C _1-4 alkoxy radiolabeled with ¹¹ C or ¹⁸ F.
[5] R ¹ may be substituted ¹¹ CH ₃ O—, optionally substituted ¹⁸ FCH ₂ O—, optionally substituted ¹⁸ FCD ₂ O—, optionally substituted ¹⁸ The compound or a salt thereof according to [1], which is FCH ₂ CH ₂ O— or optionally ¹⁸ FCD ₂ CD ₂ O—.
[6] R ¹ is optionally substituted ¹¹ CH ₃ O—, optionally substituted ¹⁸ FCD ₂ O—, or optionally ¹⁸ FCD ₂ CD ₂ O—, [1] Or a salt thereof.
[7] The compound or a salt thereof according to [1], wherein both m and n are 0.
[8] The compound or a salt thereof according to [2], wherein ring A ′ is benzene optionally substituted with one halogen atom.
[9] Ring B is
The compound or a salt thereof according to [2], selected from the group consisting of (1) optionally substituted tetrahydropyranyl and (2) optionally substituted azetidinyl.
[10] 1- [2-fluoro-4- (tetrahydro -2H- pyran-4-yl) phenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine - 4 (1H) -one or a salt thereof.
[11] 1- [4- (3,3-difluoro-1-yl) -2-fluorophenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) Pyridazin-4 (1H) -one or a salt thereof.
[12] 5-([ ¹⁸ F] fluoro-methyloxy-d ₂ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H -Pyrazol-5-yl) pyridazin-4 (1H) -one or a salt thereof.
[13] 5- (2- [ ¹⁸ F] fluoro-ethyloxy-d ₄ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl- 1H-pyrazol-5-yl) pyridazin-4 (1H) -one or a salt thereof.
[14] A method for quantitatively imaging PDE10A in a mammal , comprising administering an effective amount of the compound of [1] or a salt thereof to a mammal in need of such imaging, and positron emission tomography Using imaging to obtain an image useful for quantifying PDE10A in said mammal.
[15] A method for quantitatively imaging PDE10A in the brain of a mammal , comprising administering an effective amount of the compound of [1] or a salt thereof to a mammal in need of such imaging; Obtaining images useful for quantifying PDE10A in the brain in the mammal using emission tomography.
[16] A method for imaging diagnosis of a neurological or psychiatric disorder associated with PDE10A dysfunction in mammals , wherein an effective amount of the compound of [1] or a salt thereof is administered to a mammal in need of such imaging And obtaining images useful for quantifying PDE10A in the mammalian brain using positron emission tomography.
[17] A method for imaging a neurological or psychiatric disorder associated with decreased striatal function or basal ganglia dysfunction in mammals , wherein an effective amount of [1] is applied to a mammal in need of such imaging Administering a compound or salt thereof and obtaining an image useful for quantifying PDE10A in the brain of said mammal using positron emission tomography.
[18] A method for quantifying PDE10A in mammalian tissue, comprising contacting such mammalian tissue desired to be quantified with an effective amount of a compound of [1] or a salt thereof, and positron emission tomography Detecting or quantifying PDE10A using a method.
[19] A sterile composition comprising the compound of [1] or a salt thereof dissolved in physiological saline.
[20] Use of the compound of [1] or a salt thereof for imaging a tissue, cell or host in vitro or in vivo.
[21] A method for imaging a tissue, cell or host, comprising contacting the compound of [1] or a salt thereof with the tissue, cell or host, or administering to the tissue, cell or host, and PET imaging Imaging the tissue, cell or host in the system.
[22] The compound of [1] or a salt thereof used for quantitative imaging of PDE10A.
About.

  According to the present invention, a novel radiolabeled compound useful as a radiotracer for quantitatively imaging PDE10A in mammals can be provided.

FIG. 1 shows the parent fraction of the radioligand of Example 2. FIG. 2 shows the parent fraction of the radioligand of Example 3. FIG. 3 shows whole brain uptake of Examples 2 and 3 (% ID, 2 rhesus monkeys). FIG. 4 shows the whole brain uptake of Examples 2 and 3 (% SUV, 2 rhesus monkeys). FIG. 5 shows the local brain uptake of Example 2 (% SUV). FIG. 6 shows the local brain uptake of Example 3 (% SUV). FIG. 7 shows the time course of specific radioligand binding of Example 2. FIG. 8 shows the time course of specific radioligand binding of Example 3. FIG. 9 shows the change with time of the ratio of the target area to the reference area (Example 2). FIG. 10 shows the change over time in the ratio of the target area to the reference area (Example 3). FIG. 11 shows the parent fraction of the radioligand of Example 119. FIG. 12 shows the parent fraction of the radioligand of Example 120. FIG. 13 shows whole brain uptake of Examples 119 and 120 (% ID, 3 cynomolgus monkeys). FIG. 14 shows whole brain uptake of Examples 119 and 120 (% SUV, 3 cynomolgus monkeys). FIG. 15 shows the regional brain uptake of Example 119 (% SUV). FIG. 16 shows the local brain uptake of Example 120 (% SUV). FIG. 17 shows the time course of specific radioligand binding of Example 119. FIG. 18 shows the time course of specific radioligand binding of Example 120. FIG. 19 shows the change with time of the ratio of the target area to the reference area (Example 119). FIG. 20 shows the change with time of the ratio of the target area to the reference area (Example 120).

(Detailed description of the invention)
The present invention is described in detail below.
In the present specification, unless otherwise specified, examples of the “halogen” include fluorine, chlorine, bromine and iodine.
In the present specification, unless otherwise specified, “optionally halogenated” or “halogeno” may include one or more (eg, 1 to 3) halogen atoms as a substituent. Means good.

In the present specification, unless otherwise specified, examples of the “alkyl (group)” include C _1-10 alkyl (group), preferably C _1-6 alkyl (group).
In the present specification, unless otherwise specified, examples of the “C _1-10 alkyl (group)” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl and hexyl are mentioned. In the present specification, “C _1-6 alkyl (group)” is an alkyl having 1 to 6 carbon atoms in the above “C _1-10 alkyl (group)”, and “C _1-4 alkyl ( "Group)" is an alkyl having 1 to 4 carbon atoms in the above "C _1-10 alkyl (group)".
In the present specification, unless otherwise specified, the “optionally halogenated C _1-10 alkyl (group)” means a C _1-10 alkyl (group) _optionally substituted with halogen. Examples thereof include trifluoromethyl.

In the present specification, unless otherwise specified, examples of the “alkenyl (group)” include C _2-6 alkenyl (group).
In the present specification, unless otherwise specified, examples of the “C _2-6 alkenyl (group)” include vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-butene. Examples include -1-yl, 4-penten-1-yl, and 5-hexen-1-yl. In the present specification, “C _2-4 alkenyl (group)” is alkenyl having 2 to 4 carbon atoms in the above “C _2-6 alkenyl (group)”.

In the present specification, unless otherwise specified, examples of the “alkynyl (group)” include a C _2-6 alkynyl group.
Examples of “C _2-6 alkynyl (group)” include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentyn-1-yl, and 5-hexyn-1-yl. Is mentioned. In the present specification, “C _2-4 alkynyl (group)” is alkynyl having 2 to 4 carbon atoms in the above “C _2-6 alkynyl (group)”.
In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkyl-C _2-6 alkynyl (group)” include cyclopropylethyl.

In the present specification, unless otherwise specified, examples of the “C _3-12 cycloalkyl (group)” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In the present specification, “C _3-7 cycloalkyl (group)” is cycloalkyl having 3 to 7 carbon atoms in the above “C _3-12 cycloalkyl (group)”.

In the present specification, unless otherwise specified, examples of the “C _6-14 aryl (group)” include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, and 2 -Anthryl.

In the present specification, unless otherwise specified, examples of the “C _7-16 aralkyl (group)” include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, Examples include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl, and 4-biphenylmethyl. In the present specification, “C _7-14 aralkyl (group)” is an aralkyl having 7 to 14 carbon atoms in the above “C _7-16 aralkyl (group)”.

In the present specification, unless otherwise specified, examples of the “C _6-14 aryl-C _2-6 alkenyl (group)” include styryl.

In the present specification, unless otherwise specified, the “cyclic group” includes “C _3-12 cycloalkyl (group)” (preferably C _3-7 cycloalkyl), “C _6-14 aryl (group)”. And “heterocyclic group”.
In the present specification, unless otherwise specified, the “heterocyclic group” (and the heterocyclic group in the substituent) is a non-aromatic heterocyclic group or a heteroaryl group (that is, an aromatic heterocyclic group). Examples thereof include a 3 to 14 membered heterocyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. The “heterocyclic group” may be monocyclic, bicyclic or tricyclic.

Examples of such “3 to 14-membered heterocyclic group” include pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (eg, 3- Isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), thiazolyl (eg, 2 -Thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (eg 1, 2 3-triazol-4-yl, 1,2,4-triazol-3-yl), oxadiazolyl (eg, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazole-5) -Yl), thiadiazolyl (eg, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl) ), Pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, indolyl, isoindolyl (eg, 1-isoindolyl, 2-isoindolyl, 3- Isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indri (Eg, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo [b] furanyl (eg, 2-benzo [b] furanyl, 3- Benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), benzo [c] furanyl (eg, 1-benzo [C] furanyl, 4-benzo [c] furanyl, 5-benzo [c] furanyl), benzo [b] thienyl, (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [B] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), benzo [c] thienyl (eg, 1-benzo [c] thienyl, 4-benzo [ c] Enyl, 5-benzo [c] thienyl), indazolyl (eg, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (eg, 1-indazolyl) Benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzoimidazolyl), 1,2-benzisoxazolyl (eg, 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl) 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzoxazolyl (eg, 2-benzoxazolyl) , 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazo 7-benzoxazolyl), 1,2-benzisothiazolyl (eg, 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzo Isothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,2-benzisothiazol-7-yl), benzothiazolyl (eg, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6- Benzothiazolyl, 7-benzothiazolyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8- Quinolyl), cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolini 7-cinnolinyl, 8-cinnolinyl), phthalazinyl (eg, 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-phthalazinyl), quinazolinyl (eg, 2-quinazolinyl, 4-quinazolinyl) , 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (eg, 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8-quinoxalinyl), pyrazolo [1 , 5-a] pyridyl (eg, pyrazolo [1,5-a] pyridin-2-yl, pyrazolo [1,5-a] pyridin-3-yl, pyrazolo [1,5-a] pyridin-4-yl Pyrazolo [1,5-a] pyridin-5-yl, pyrazolo [1,5-a] pi Lysine-6-yl, pyrazolo [1,5-a] pyridin-7-yl), imidazo [1,2-a] pyridyl (eg, imidazo [1,2-a] pyridin-2-yl, imidazo [1 , 2-a] pyridin-3-yl, imidazo [1,2-a] pyridin-5-yl, imidazo [1,2-a] pyridin-6-yl, imidazo [1,2-a] pyridine-7 A 3- to 14-membered aromatic heterocyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, such as -yl, imidazo [1,2-a] pyridin-8-yl); , Tetrahydrofuryl, oxazolidinyl, imidazolinyl (eg, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridinyl (eg, 1-aziridinyl, 2-aziridinyl), azetidinyl (eg, 1-azetidinyl) 2-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), piperidinyl (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), azepanyl (eg, 1-azepanyl, 2- Azepanyl, 3-azepanyl, 4-azepanyl), azocanyl (eg, 1-azocanyl, 2-azocanyl, 3-azocanyl, 4-azocanyl), piperazinyl (eg, 1,4-piperazin-1-yl, 1,4- Piperazin-2-yl), diazepinyl (eg, 1,4-diazepin-1-yl, 1,4-diazepin-2-yl, 1,4-diazepin-5-yl, 1,4-diazepin-6-yl) ), Diazocanyl (eg, 1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1, -Diazocan-6-yl, 1,5-diazocan-1-yl, 1,5-diazocan-2-yl, 1,5-diazocan-3-yl), tetrahydropyranyl (eg, tetrahydropyran-4-yl) ), Morpholinyl (eg, 4-morpholinyl), thiomorpholinyl (eg, 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihydropyranyl, dihydropyrazolyl, dihydropyrrolyl, dihydroquinolyl, oxaazabicyclooctyl and oxazepanyl And saturated or unsaturated, 3 to 14 membered non-aromatic heterocyclic group having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen.

  In the present specification, unless otherwise specified, examples of the “5- to 10-membered heterocyclic group” include 5- to 10-membered members among the “3 to 14-membered heterocyclic group”.

  In the present specification, unless otherwise specified, examples of the “aromatic heterocyclic group” (and the aromatic heterocyclic moiety in the substituent) include, for example, “nitrogen, And a 3 to 14 membered aromatic heterocyclic group having 1 to 5 heteroatoms selected from sulfur and oxygen.

  Unless otherwise specified, in this specification, examples of the “non-aromatic heterocyclic group” (and the aromatic heterocyclic moiety in the substituent) include, for example, “nitrogen” exemplified above for the “heterocyclic group”. , Saturated or unsaturated, 3 to 14 membered non-aromatic heterocyclic group having 1 to 5 heteroatoms selected from sulfur and oxygen.

In the present specification, unless otherwise specified, examples of the “saturated heterocyclic group” (and the saturated heterocyclic moiety in the substituent) include, for example, saturated ones of the “non-aromatic heterocyclic group”, specifically Specific examples include tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl groups.
In the present specification, unless otherwise specified, examples of the “5- to 6-membered saturated heterocyclic group” (and the saturated heterocyclic moiety in the substituent) include 5 to 5 of the “saturated heterocyclic group”. 6 members are listed.

In the present specification, unless otherwise specified, examples of the “alkoxy (group)” include C _1-10 alkoxy (group).
In the present specification, unless otherwise specified, examples of the “C _1-10 alkoxy (group)” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy. It is done. In the present specification, “C _1-4 alkoxy (group)” is alkoxy having 1 to 4 carbon atoms in the above “C _1-10 alkoxy (group)”.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkyloxy (group)” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

In the present specification, unless otherwise specified, examples of the “C _6-14 aryloxy (group)” include phenyloxy, 1-naphthyloxy, and 2-naphthyloxy.

In the present specification, unless otherwise specified, examples of the “C _7-16 aralkyloxy (group)” include benzyloxy and phenethyloxy.

In the present specification, unless otherwise specified, examples of the “alkyl-carbonyloxy (group)” include C _1-10 alkyl-carbonyloxy (group).
In the present specification, unless otherwise specified, examples of the “C _1-10 alkyl-carbonyloxy (group)” include acetoxy and propionyloxy.

In the present specification, unless otherwise specified, examples of the “alkoxy-carbonyloxy (group)” include C _1-10 alkoxy-carbonyloxy (group).
In the present specification, unless otherwise specified, examples of the “C _1-10 alkoxy-carbonyloxy (group)” include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy and butoxycarbonyloxy.

In the present specification, unless otherwise specified, examples of the “mono-alkyl-carbamoyloxy (group)” include mono-C _1-10 alkyl-carbamoyloxy (group).
In the present specification, unless otherwise specified, examples of the “mono-C _1-10 alkyl-carbamoyloxy (group)” include methylcarbamoyloxy and ethylcarbamoyloxy.

In the present specification, unless otherwise specified, examples of the “di-alkyl-carbamoyloxy (group)” include di-C _1-10 alkyl-carbamoyloxy (group).
In the present specification, unless otherwise specified, examples of the “di-C _1-10 alkyl-carbamoyloxy (group)” include dimethylcarbamoyloxy and diethylcarbamoyloxy (group).

Unless otherwise specified, in this specification, examples of the “C _6-14 aryl-carbonyloxy (group)” include benzoyloxy and naphthylcarbonyloxy.

In the present specification, unless otherwise specified, examples of the “mono- or di-C _6-14 aryl-carbamoyloxy (group)” include phenylcarbamoyloxy and naphthylcarbamoyloxy.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocyclic-oxy (group)” include those similar to the aforementioned “heterocyclic group”. Specific examples of the “heterocycle-oxy (group)” include a 5- to 14-membered heterocycle-oxy (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. .

  In the present specification, unless otherwise specified, examples of the aromatic heterocyclic moiety of “heterocyclic-oxy (group)” include “aromatic heterocyclic group” as an example of the above-mentioned “heterocyclic group”. The same thing is mentioned. Specifically, as the “aromatic heterocyclic-oxy (group)”, for example, a 3 to 14-membered aromatic heterocyclic-oxy (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen ).

In the present specification, unless otherwise specified, examples of the “C _1-10 alkylsulfonyloxy (group)” include methylsulfonyloxy and ethylsulfonyloxy.

In the present specification, unless otherwise specified, examples of the “halogeno C _1-10 alkylsulfonyloxy (group)” include halogenomethylsulfonyloxy and halogenoethylsulfonyloxy.

In the present specification, unless otherwise specified, examples of the “alkylsulfanyl (group)” include C _1-10 alkylsulfanyl (group).
Unless otherwise specified, in this specification, examples of the “C _1-10 alkylsulfanyl (group)” include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, and tert- Butylsulfanyl is mentioned.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkylsulfanyl (group)” include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl and cyclohexylsulfanyl.

Unless otherwise specified, in this specification, examples of the “C _6-14 arylsulfanyl (group)” include phenylsulfanyl, 1-naphthylsulfanyl and 2-naphthylsulfanyl.

In the present specification, unless otherwise specified, examples of the “C _7-16 aralkylsulfanyl (group)” include benzylsulfanyl and phenethylsulfanyl.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocycle-sulfanyl (group)” include those similar to the aforementioned “heterocyclic group”. Specific examples of the “heterocycle-sulfanyl (group)” include a 5- to 14-membered heterocycle-sulfanyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. .

In the present specification, unless otherwise specified, examples of the “alkyl-carbonyl (group)” include C _1-10 alkyl-carbonyl.
In the present specification, unless otherwise specified, examples of the “C _1-10 alkyl-carbonyl (group)” include acetyl, propionyl and pivaloyl.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkyl-carbonyl (group)” include cyclopropylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl groups.

Unless otherwise specified, in this specification, examples of the “C _6-14 aryl-carbonyl (group)” include benzoyl, 1-naphthoyl and 2-naphthoyl groups.

In the present specification, unless otherwise specified, examples of the “C _7-16 aralkyl-carbonyl (group)” include phenylacetyl and 3-phenylpropionyl groups.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocycle-carbonyl (group)” include those similar to the above-mentioned “heterocyclic group”. Specific examples include 3 to 14-membered heterocycle-carbonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen, and more specifically, for example, picolinoyl, nicotinoyl, Isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, aziridin-1-ylcarbonyl, aziridin-2-ylcarbonyl, azetidine-1 -Ylcarbonyl, azetidin-2-ylcarbonyl, pyrrolidin-1-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, piperidin-1-ylcarbonyl, piperidin-2-ylcarbonyl, piperidin-3- Ylcarbonyl, azepan-1-ylcarbonyl, azepan-2 Ylcarbonyl, azepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcarbonyl, azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-4-ylcarbonyl, 1,4-piperazine -1-ylcarbonyl, 1,4-piperazin-2-ylcarbonyl, 1,4-diazepan-1-ylcarbonyl, 1,4-diazepan-2-ylcarbonyl, 1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6-ylcarbonyl, 1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2-ylcarbonyl, 1,4-diazocan-5-ylcarbonyl, 1,4-diazocan- 6-ylcarbonyl, 1,5-diazocan-1-ylcarbonyl, 1,5-diazocan-2-yl Carbonyl and 1,5-diazocan-3-ylcarbonyl and the like.

In the present specification, unless otherwise specified, examples of the “optionally esterified carboxy (group)” include carboxy, optionally substituted alkoxy-carbonyl, and optionally substituted C _{6-6. 14} aryloxy-carbonyl, optionally substituted C _7-16 aralkyloxy-carbonyl, optionally substituted silyloxy-carbonyl (eg, TMS-O—CO—, TES—O—CO—, TBS—O) -CO-, TIPS-O-CO-, TBDPS-O-CO-, etc.).

  In the present specification, unless otherwise specified, examples of the “alkoxy-carbonyl (group)” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.

In the present specification, unless otherwise specified, examples of the “C _6-14 aryloxy-carbonyl (group)” include phenoxycarbonyl.
In the present specification, unless otherwise specified, examples of the “C _7-16 aralkyloxy-carbonyl (group)” include benzyloxycarbonyl and phenethyloxycarbonyl.

In the present specification, unless otherwise specified, examples of the “alkylsulfonyl (group)” include C _1-10 alkylsulfonyl (group).
In the present specification, unless otherwise specified, examples of the “C _1-10 alkylsulfonyl (group)” include methylsulfonyl and ethylsulfonyl.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkylsulfonyl (group)” include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, and cyclohexylsulfonyl.

In the present specification, unless otherwise specified, examples of the “C _6-14 arylsulfonyl (group)” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocycle-sulfonyl (group)” include those similar to the above-mentioned “heterocyclic group”. Specific examples of the “heterocycle-sulfonyl (group)” include a 5- to 14-membered heterocycle-sulfonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. .

  In the present specification, unless otherwise specified, examples of the saturated heterocyclic moiety of the “saturated heterocyclic-sulfonyl (group)” include those similar to the aforementioned “heterocyclic group”. Specific examples of the “heterocycle-sulfonyl (group)” include a 5- to 14-membered heterocycle-sulfonyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. .

In the present specification, unless otherwise specified, examples of the “alkylsulfinyl (group)” include C _1-10 alkylsulfinyl (group).

In the present specification, unless otherwise specified, examples of the “C _1-10 alkylsulfinyl (group)” include methylsulfinyl and ethylsulfinyl.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkylsulfinyl (group)” include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, and cyclohexylsulfinyl.

In the present specification, unless otherwise specified, examples of the “C _6-14 arylsulfinyl (group)” include phenylsulfinyl, 1-naphthylsulfinyl and 2-naphthylsulfinyl.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocycle-sulfinyl (group)” include those similar to the above-mentioned “heterocyclic group”. Specific examples of the “heterocycle-sulfinyl (group)” include a 5- to 14-membered heterocycle-sulfinyl (group) having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen. .

In the present specification, unless otherwise specified, examples of the “alkyl-carbamoyl (group)” include C _1-10 alkyl-carbamoyl (group).

Unless otherwise specified, in this specification, examples of the “C _1-10 alkyl-carbamoyl (group)” include methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl.

In the present specification, unless otherwise specified, examples of the “mono- or di-alkylamino (group)” include mono- or di-C _1-10 alkylamino (group).

In the present specification, unless otherwise specified, examples of the “mono- or di-C _1-10 alkylamino (group)” include methylamino, ethylamino, propylamino, dimethylamino and diethylamino.

In the present specification, unless otherwise specified, examples of the “alkyl-carbonylamino (group)” include C _1-10 alkyl-carbonylamino.

In the present specification, unless otherwise specified, examples of the “C _1-10 alkyl-carbonylamino (group)” include acetylamino, propionylamino, and pivaloylamino.

  In the present specification, unless otherwise specified, examples of the heterocyclic moiety of the “heterocyclic-amino (group)” include those similar to the above-mentioned “heterocyclic group”. Examples of the “heterocycle-amino (group)” include 2-pyridyl-amino.

  In the present specification, unless otherwise specified, examples of the “heterocycle-carbonyl” of the “heterocycle-carbonylamino (group)” include those similar to the above-mentioned “heterocycle-carbonyl”. Examples of the “heterocycle-carbonylamino (group)” include pyridyl-carbonylamino.

  In the present specification, unless otherwise specified, examples of the “heterocycle (group)” of the “heterocycle-oxycarbonylamino (group)” include those similar to the above-mentioned “heterocycle group”. Examples of the “heterocycle-oxycarbonylamino (group)” include 2-pyridyl-oxycarbonylamino.

  In the present specification, unless otherwise specified, examples of the “heterocycle (group)” of the “heterocycle-sulfonylamino (group)” include the same as the above-mentioned “heterocycle group”. Examples of the “heterocycle-sulfonylamino (group)” include 2-pyridyl-sulfonylamino.

In the present specification, unless otherwise specified, examples of the “alkoxy-carbonylamino (group)” include C _1-10 alkoxy-carbonylamino.

In the present specification, unless otherwise specified, examples of the “C _1-10 alkoxy-carbonylamino (group)” include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, and butoxycarbonylamino.

In the present specification, unless otherwise specified, examples of the “alkylsulfonylamino (group)” include C _1-10 alkylsulfonylamino.

In the present specification, unless otherwise specified, examples of the “C _1-10 alkylsulfonylamino (group)” include methylsulfonylamino and ethylsulfonylamino.

In the present specification, unless otherwise specified, examples of the “mono- or di-C _3-7 cycloalkylamino (group)” include cyclopropylamino, cyclopentylamino, and cyclohexylamino.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkyl-carbonylamino (group)” include cyclopropylcarbonylamino, cyclopentylcarbonylamino, and cyclohexylcarbonylamino.

Unless otherwise specified, in this specification, examples of the “C _3-7 cycloalkyloxy-carbonylamino (group)” include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, and cyclohexyloxycarbonylamino.

In the present specification, unless otherwise specified, examples of the “C _3-7 cycloalkyl-sulfonylamino (group)” include cyclopropylsulfonylamino, cyclopentylsulfonylamino, and cyclohexylsulfonylamino.

In the present specification, unless otherwise specified, examples of the “mono- or di-C _6-14 arylamino (group)” include phenylamino and diphenylamino.

In the present specification, unless otherwise specified, examples of the “mono- or di-C _7-16 aralkylamino (group)” include benzylamino.

In the present specification, unless otherwise specified, examples of the “C _6-14 aryl-carbonylamino (group)” include benzoylamino and naphthoylamino.

In the present specification, unless otherwise specified, examples of the “C _6-14 arylsulfonylamino (group)” include phenylsulfonylamino, 2-naphthylsulfonylamino, and 1-naphthylsulfonylamino.

  In the present specification, unless otherwise specified, when a group, a moiety, and a ring described in the present specification are substituted with a plurality of substituents, each substituent may be the same or different.

Herein, unless otherwise specified, "optionally substituted C _1-4 alkyl", "optionally substituted C _1-4 alkoxy", "optionally substituted C _7-14 “Aralkyl”, “optionally substituted C _3-7 cycloalkyl”, “ _optionally substituted C _2-4 alkenyl”, “optionally substituted C _2-4 alkynyl”, “substituted” _Optionally substituted cyclic group "," optionally substituted C _3-12 cycloalkyl "," optionally substituted dihydropyranyl "," optionally substituted tetrahydropyranyl "," substituted “Optionally substituted azetidinyl”, “optionally substituted pyrrolidinyl”, “optionally substituted piperidinyl”, “optionally substituted imidazolyl”, “optionally substituted isoxazolyl” , “Optionally substituted pyrazolyl”, “optionally substituted dihydropyrazolyl”, “optionally substituted pyridyl”, “optionally substituted pyrrolyl”, “optionally substituted dihydro “Pyrrolyl”, “optionally substituted phenyl”, “optionally substituted morpholinyl”, “optionally substituted thiazolyl”, “optionally substituted oxazolidinyl”, “optionally substituted” “Good imidazolidinyl”, “optionally substituted oxaazabicyclooctyl”, “optionally substituted oxazepanyl” and “optionally substituted formula”

Examples of the substituent of the “group represented by” include substituents selected from the following substituent group A. The number of the substituents is 1 to the maximum number that can be substituted, preferably 1 to 3, and more preferably 1.

[Substituent group A]
(1) a halogen atom;
(2) a nitro group;
(3) a cyano group;
(4) an optionally esterified carboxy group;
(5) an optionally substituted alkyl group;
(6) an alkenyl group which may be substituted;
(7) an optionally substituted alkynyl group (eg, an optionally substituted C _3-7 cycloalkyl-C _2-6 alkynyl group);
(8) an optionally substituted C _3-7 cycloalkyl group;
(9) an optionally substituted C _6-14 aryl group;
(10) an optionally substituted C _7-16 aralkyl group;
(11) an optionally substituted C _6-14 aryl-C _2-6 alkenyl group;
(12) an optionally substituted heterocyclic group;
(13) a hydroxy group;
(14) an optionally substituted alkoxy group;
(15) an optionally substituted C _3-7 cycloalkyloxy group;
(16) an optionally substituted C _6-14 aryloxy group;
(17) an optionally substituted C _7-16 aralkyloxy group;
(18) an optionally substituted alkyl-carbonyloxy group;
(19) an optionally substituted alkoxy-carbonyloxy group;
(20) an optionally substituted mono-alkyl-carbamoyloxy group;
(21) an optionally substituted di-alkyl-carbamoyloxy group;
(22) an optionally substituted C _6-14 aryl-carbonyloxy group;
(23) an optionally substituted mono- or di-C _6-14 aryl-carbamoyloxy group;
(24) An optionally substituted heterocyclic-oxy group (eg, an optionally substituted aromatic heterocyclic-oxy group);
(25) an optionally substituted C _1-10 alkylsulfonyloxy (group) (eg, optionally substituted halogeno C _1-10 alkylsulfonyloxy (group));
(26) mercapto group;
(27) an optionally substituted alkylsulfanyl group;
(28) an optionally substituted C _3-7 cycloalkylsulfanyl group;
(29) an optionally substituted C _6-14 arylsulfanyl group;
(30) an optionally substituted C _7-16 aralkylsulfanyl group;
(31) an optionally substituted heterocyclic-sulfanyl group;
(32) formyl group;
(33) an optionally substituted alkyl-carbonyl group;
(34) an optionally substituted C _3-7 cycloalkylcarbonyl group;
(35) an optionally substituted C _6-14 arylcarbonyl group;
(36) an optionally substituted C _7-16 aralkylcarbonyl group;
(37) an optionally substituted heterocyclic-carbonyl group;
(38) an optionally substituted alkylsulfonyl group;
(39) an optionally substituted C _3-7 cycloalkylsulfonyl group;
(40) an optionally substituted C _6-14 arylsulfonyl group;
(41) an optionally substituted heterocyclic-sulfonyl group;
(42) an optionally substituted alkylsulfinyl group;
(43) an optionally substituted C _3-7 cycloalkylsulfinyl group;
(44) an optionally substituted C _6-14 arylsulfinyl group;
(45) an optionally substituted heterocyclic-sulfinyl group;
(46) a sulfo group;
(47) a sulfamoyl group;
(48) a sulfinamoyl group;
(49) Sulphenamoyl group;
(50) a thiocarbamoyl group;
(51) an optionally substituted carbamoyl group [eg, an optionally substituted alkyl-carbamoyl group];
(52) an optionally substituted amino group [eg,
amino,
An optionally substituted mono- or di-alkylamino group,
An optionally substituted mono- or di-C _3-7 cycloalkylamino group,
An optionally substituted mono- or di-C _6-14 arylamino group,
An optionally substituted mono- or di-C _7-16 aralkylamino group,
An optionally substituted heterocyclic amino group,
An optionally substituted C _6-14 aryl-carbonylamino group,
Formylamino,
An optionally substituted alkyl-carbonylamino group (eg, an optionally substituted mono- (C _1-10 alkyl-carbonyl) -amino group),
An optionally substituted C _3-7 cycloalkyl-carbonylamino group,
Optionally substituted heterocycle-carbonylamino group,
An optionally substituted C _3-7 cycloalkyloxy-carbonylamino group,
Optionally substituted heterocycle-oxycarbonylamino group,
An optionally substituted carbamoylamino group,
An optionally substituted alkoxy-carbonylamino group,
An optionally substituted alkylsulfonylamino group,
An optionally substituted C _3-7 cycloalkyl-sulfonylamino group,
An optionally substituted heterocyclic sulfonylamino group,
C _6-14 arylsulfonylamino group which may be substituted]

Substituent group A above, i.e., in particular,
“Optionally substituted alkoxy-carbonyl group”,
"Optionally substituted alkyl group",
“Optionally substituted alkenyl group”,
“Optionally substituted alkynyl group”,
“Optionally substituted alkoxy group”,
"Optionally substituted alkyl-carbonyloxy group",
“Optionally substituted alkoxy-carbonyloxy group”,
“Optionally substituted mono-alkyl-carbamoyloxy group”,
“Optionally substituted di-alkyl-carbamoyloxy group”,
“C _1-10 alkylsulfonyloxy group which may be substituted”,
“Optionally substituted halogeno C _1-10 alkylsulfonyloxy group”,
"Optionally substituted alkylsulfanyl group",
"Optionally substituted alkyl-carbonyl group",
"Optionally substituted alkylsulfonyl group",
"Optionally substituted alkylsulfinyl group",
"Optionally substituted alkyl-carbamoyl group",
“Optionally substituted mono- or di-alkylamino group”,
“Optionally substituted alkyl-carbonylamino group”,
“Optionally substituted mono- (C _1-10 alkyl-carbonyl) -amino group”,
“Optionally substituted carbamoylamino group”,
Examples of the substituent of the “optionally substituted alkoxy-carbonylamino group” and the “optionally substituted alkylsulfonylamino group” include a substituent selected from the following substituent group B. . The number of the substituents is 1 to the maximum number that can be substituted, preferably 1 to 3, and more preferably 1.

[Substituent group B]
Substituent group B is
(a) a halogen atom;
(b) a hydroxy group;
(c) a nitro group;
(d) a cyano group;
(e) an optionally substituted C _6-14 aryl group (the “C _6-14 aryl group” is halogen, hydroxy, cyano, amino, optionally halogenated C _1-10 alkyl, mono- Or di-C _1-10 alkylamino, mono-, or di-C _6-14 arylamino, mono-, or di-C _7-16 aralkylamino, C _3-7 cycloalkyl, C _1-10 alkoxy, Formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _{6-14 aryloxy- carbonyl, C 7-16} aralkyloxy - _{carbonyl, C 1-10 alkylsulfanyl, C 1-10} alkylsulfinyl, C _-10 alkylsulfonyl, carbamoyl, thiocarbamoyl, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like (preferably 1 to 3 And more preferably 1)));
(f) an optionally substituted C _6-14 aryloxy group (the “C _6-14 aryloxy group” is halogen, hydroxy, cyano, amino, optionally halogenated C _1-10 alkyl, Mono-, or di-C _1-10 alkylamino, mono-, or di-C _6-14 arylamino, mono-, or di-C _7-16 aralkylamino, C _3-7 cycloalkyl, C _1-10 Alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _6-14 aryl oxy - _{carbonyl, C 7-16} aralkyloxy - _{carbonyl, C 1-10 alkylsulfanyl, C 1-10} alkylsulfamoyl _{Iniru, C 1-10} alkylsulfonyl, carbamoyl, thiocarbamoyl, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like (preferably Is optionally substituted with 1 to 3 substituents, more preferably 1);
(g) an optionally substituted C _7-16 aralkyloxy group (the “C _7-16 aralkyloxy group” is a halogen atom, hydroxy, cyano, amino, optionally halogenated C _1-10 alkyl; , Mono-, or di-C _1-10 alkylamino, mono-, or di-C _6-14 arylamino, mono-, or di-C _7-16 aralkylamino, C _3-7 cycloalkyl, C _{1- 10} alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _6-14 aryloxy - _{carbonyl, C 7-16} aralkyloxy - _{carbonyl, C 1-10 alkylsulfanyl, C 1-10} Al _{Rusurufiniru, C 1-10} alkylsulfonyl, carbamoyl, thiocarbamoyl, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like ( Preferably 1 to 3 and more preferably 1) may be substituted with a substituent);
(h) an optionally substituted mono- or di-5- to 10-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (eg, furyl, pyridyl, thienyl, Pyrrolidino, 1-piperidinyl, 4-piperidyl, piperazinyl, 1-morpholinyl, 4-thiomorpholinyl, azepan-1-yl, azocan-1-yl, azonan-1-yl, 3,4-dihydroisoquinolin-2-yl, etc.) (The "mono- or di-5- to 10-membered heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen" is halogenated, hydroxy, cyano, amino, halogenated. C _1-10 alkyl, mono-, or di-C _1-10 alkylamino, mono-, or di-C _6-14 arylamino, mono-, or di-C _7-16 aralkyl Ruamino, C _3-7 cycloalkyl, C _1-10 alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy - _{carbonyl, C 6-14} aryloxy - _{carbonyl, C 7-16} aralkyloxy - _{carbonyl, C 1-10 alkylsulfanyl, C 1-10 alkylsulfinyl, C 1-10} alkylsulfonyl, carbamoyl, thio One or more selected from carbamoyl, mono-, or di-C _1-10 alkylcarbamoyl, mono-, or di-C _6-14 aryl-carbamoyl (preferably 1 to 3, more preferably 1) Which may be substituted with a substituent of
(i) an optionally substituted amino group [for example, a group consisting of C _1-10 alkyl, C _2-6 alkenyl, C _6-14 aryl, C _7-16 aralkyl, a heterocyclic group, and a heterocyclic-alkyl group; An amino group which may be substituted with one or two substituents selected from (the C _1-10 alkyl, C _2-6 alkenyl, C _6-14 aryl, C _7-16 aralkyl, heterocyclic group and Heterocycle-alkyl groups are each a halogen atom, hydroxy, cyano, amino, optionally halogenated C _1-10 alkyl (but not alkyl and alkenyl substituents), mono-, or di-C _{1- 10} alkylamino, mono - or di _{-C 6-14} arylamino, mono- - or di _{-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-10} alkoxy , _{Formyl, C 1-10} alkyl - _{carbonyl, C 3-7} cycloalkyl - _{carbonyl, C 6-14} aryl - _{carbonyl, C 7-16} aralkyl - _{carbonyl, C 1-10} alkoxy - _{carbonyl, C 3-7} cycloalkyl Oxy-carbonyl, C _6-14 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, C _1-10 alkylsulfanyl, C _3-7 cycloalkylsulfanyl, C _1-10 alkylsulfinyl, C _3-7 cycloalkyl Substituted with sulfinyl, C _1-10 alkylsulfonyl, C _3-7 cycloalkylsulfonyl, carbamoyl, thiocarbamoyl, mono-, or di-C _1-10 alkylcarbamoyl, mono-, or di-C _6-14 aryl-carbamoyl May be). The “heterocycle” of “heterocycle” and “heterocycle-alkyl” includes the same as the above “heterocycle group”. ];
(j) C _3-7 cycloalkyl;
(k) optionally substituted C _1-10 alkoxy (wherein “C _1-10 alkoxy” is halogen, hydroxy, amino, mono-, or di-C _1-10 alkylamino, mono-, or di- C _6-14 arylamino, C _3-7 cycloalkyl, C _1-10 alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl-carbonyl, C _6-14 aryl-carbonyl, C _{7- 16} aralkyl - _{carbonyl, C 1-10} alkoxy - _{carbonyl, C 6-14} aryloxy - _{carbonyl, C 7-16} aralkyloxy - _{carbonyl, C 1-10 alkylsulfanyl, C 1-10 alkylsulfinyl, C 1-10} alkyl sulfonyl, carbamoyl, thiocarbamoyl, mono - or di _{-C 1-10} alkyl Cal Moil, mono - or di -C _6-14 aryl - one or more substituents selected carbamoyl and the like (preferably 1 to 3, more preferably 1) may be substituted with substituents);
(l) formyl;
(m) C _1-10 alkyl-carbonyl (eg, acetyl);
(n) C _3-7 cycloalkyl-carbonyl;
(o) C _6-14 aryl-carbonyl;
(p) C _7-16 aralkyl-carbonyl;
(q) C _1-10 alkoxy-carbonyl;
(r) C _6-14 aryloxy-carbonyl;
(s) C _7-16 aralkyloxy-carbonyl;
(t) C _1-10 alkylsulfanyl;
(u) C _1-10 alkylsulfinyl;
(v) C _1-10 alkylsulfonyl;
(w) carbamoyl;
(x) thiocarbamoyl;
(y) mono-C _1-10 alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.);
(z) di-C _1-10 alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.);
(aa) mono- or di-C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.); and
(bb) a mono- or di-5-7 membered heterocyclic-carbamoyl having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (eg, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4- Pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.)
Consists of.

In addition, the above substituent group A, that is, in particular,
“Optionally substituted C _6-14 aryloxy-carbonyl”,
“Optionally substituted C _7-16 aralkyloxy-carbonyl”,
“Optionally substituted C _3-7 cycloalkyl-C _2-6 alkynyl”,
“Optionally substituted C _3-7 cycloalkyl”,
“Optionally substituted C _6-14 aryl”,
“Optionally substituted C _7-16 aralkyl”,
“Optionally substituted C _6-14 aryl-C _2-6 alkenyl”,
"Optionally substituted heterocyclic group",
“Optionally substituted C _3-7 cycloalkyloxy”,
“Optionally substituted C _6-14 aryloxy”,
“Optionally substituted C _7-16 aralkyloxy”,
“Optionally substituted C _6-14 aryl-carbonyloxy”,
“Optionally substituted mono- or di-C _6-14 aryl-carbamoyloxy”,
“Optionally substituted heterocycle-oxy”,
“Optionally substituted aromatic heterocycle-oxy”,
“Optionally substituted C _3-7 cycloalkylsulfanyl”,
“Optionally substituted C _6-14 arylsulfanyl”,
“Optionally substituted C _7-16 aralkylsulfanyl”,
“Optionally substituted heterocycle-sulfanyl”,
“Optionally substituted C _3-7 cycloalkyl-carbonyl”,
“Optionally substituted C _6-14 aryl-carbonyl”,
“Optionally substituted C _7-16 aralkyl-carbonyl”,
“Optionally substituted heterocycle-carbonyl”,
“Optionally substituted C _3-7 cycloalkylsulfonyl”,
“Optionally substituted C _6-14 arylsulfonyl”,
“Optionally substituted heterocycle-sulfonyl”,
“Optionally substituted C _3-7 cycloalkylsulfinyl”,
“Optionally substituted C _6-14 arylsulfinyl”,
“Optionally substituted heterocycle-sulfinyl”,
“Optionally substituted carbamoyl group”,
"Optionally substituted amino group",
“Optionally substituted mono- or di-C _3-7 cycloalkylamino group”,
“Optionally substituted mono- or di-C _6-14 arylamino group”,
“Optionally substituted mono- or di-C _7-16 aralkylamino group”,
"Optionally substituted heterocyclic amino group",
“Optionally substituted C _6-14 aryl-carbonylamino group”,
“Optionally substituted C _3-7 cycloalkyl-carbonylamino group”,
“Optionally substituted heterocycle-carbonylamino group”,
“Optionally substituted C _3-7 cycloalkyloxy-carbonylamino group”,
“Optionally substituted heterocycle-oxycarbonylamino group”,
“Optionally substituted C _3-7 cycloalkyl-sulfonylamino group”,
Examples of the substituent of the “ _optionally substituted heterocyclic sulfonylamino group” and the “optionally substituted C _6-14 arylsulfonylamino group” include the above-mentioned substituent group B and And a substituent selected from the group of substituents B ′. The number of the substituents is 1 to the maximum number that can be substituted, more preferably 1 to 3, and still more preferably 1.

[Substituent group B ′ group]
Substituent group B ′ is
(a) optionally substituted C _1-10 alkyl (wherein the C _1-10 alkyl is halogen, hydroxy, cyano, amino, mono-, or di-C _1-10 alkylamino, mono-, or di- C _6-14 arylamino, mono-, or di-C _7-16 aralkylamino, C _3-7 cycloalkyl, C _1-10 alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl- Carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _6-14 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, C _1-10 alkylsulfanyl , _{C 1-10 alkylsulfinyl, C 1-10} alkylsulfonyl, carbamoyl, Chiokarubamo Le, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like (preferably 1 to 3, more preferably 1) Which may be substituted with a substituent of
(b) optionally substituted C _2-6 alkenyl (wherein the C _2-6 alkenyl is halogen, hydroxy, cyano, amino, mono-, or di-C _1-10 alkylamino, mono-, or di- C _6-14 arylamino, mono-, or di-C _7-16 aralkylamino, C _3-7 cycloalkyl, C _1-10 alkoxy, formyl, C _1-10 alkyl-carbonyl, C _3-7 cycloalkyl- Carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _6-14 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, C _1-10 alkylsulfanyl , _{C 1-10 alkylsulfinyl, C 1-10} alkylsulfonyl, carbamoyl, Chiokarubamo Le, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like (preferably 1 to 3, more preferably 1) And may be substituted with a substituent of
(c) an optionally substituted C _2-6 alkynyl (wherein the C _2-6 alkynyl is a halogen atom, hydroxy, cyano, amino, mono-, or di-C _1-10 alkylamino, mono-, or di) -C _6-14 arylamino, mono- - or di _{-C 7-16 aralkylamino, C 3-7 cycloalkyl, C 1-10} alkoxy, _{formyl, C 1-10} alkyl - _{carbonyl, C 3-7} cycloalkyl -Carbonyl, C _6-14 aryl-carbonyl, C _7-16 aralkyl-carbonyl, C _1-10 alkoxy-carbonyl, C _6-14 aryloxy-carbonyl, C _7-16 aralkyloxy-carbonyl, C _1-10 alkyl _{sulfanyl, C 1-10 alkylsulfinyl, C 1-10} alkylsulfonyl, carbamoyl, Chiokaru Moil, mono - or di _{-C 1-10} alkylcarbamoyl, mono - or di _{-C 6-14} aryl - one or more substituents selected carbamoyl and the like (preferably 1 to 3, more preferably 1) May be substituted with a substituent of
Consists of.

  Hereinafter, symbols in the above formulas (formula (I) and formula (I ′)) will be described.

In the above formula, R ¹ represents radiolabeled optionally substituted C _1-4 alkoxy.

Among them, R ¹ is preferably at least one selected from, for example, a halogen atom, a C _1-10 alkoxy group, and a C _3-7 cycloalkyl group (preferably 1 to 3, more preferably 1). ) A C _1-4 alkoxy group (eg, methoxy, ethoxy, isopropoxy, cyclopropylmethoxy, difluoromethoxy, methoxyethoxy) which may be substituted with a substituent, more preferably 1 or more (preferably 1). A C _1-4 alkoxy group which may be substituted with 3 halogen atoms (more preferably 1), and more preferably a C _1-4 alkoxy group.

The “optionally substituted C _1-4 alkoxy” represented by R ¹ is any isotope (eg, ³ H (also expressed as T), ¹¹ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, ⁸² Br, ¹²³ I, ¹³¹ I, ⁷⁵ Br, ¹⁵ O, ¹³ N, ²¹¹ At, ⁷⁷ Br, etc.) and the radiolabeled “optionally substituted C _1-4 alkoxy” is ² It may be labeled with H (also expressed as D). Preferably, “optionally substituted C _1-4 alkoxy” is labeled with an isotope selected from ¹¹ C and ¹⁸ F, and the C _1-4 alkoxy may be labeled with ² H (D). Good. In the radiolabeled “optionally substituted C _1-4 alkoxy”, either “C _1-4 alkoxy” or the “substituent” that the “C _1-4 alkoxy” may have is It may be radiolabeled. The radiolabeled “optionally substituted C _1-4 alkoxy” is preferably ¹¹ CH ₃ O— which may be substituted, ¹⁸ FCH ₂ O— which may be substituted, or which may be substituted. ¹⁸ FCD ₂ O— which may be substituted, ¹⁸ FCH ₂ CH ₂ O— which may be substituted, or ¹⁸ FCD ₂ CD ₂ O— which may be substituted, and more preferably ¹¹ CH ₃ which may be substituted it is O-, and most preferably ¹¹ CH ₃ is O-.
In another embodiment of the present invention, the radiolabeled “optionally substituted C _1-4 alkoxy” is more preferably optionally substituted, ¹¹ CH ₃ O—, ¹⁸ FCD ₂ O— or ¹⁸ FCD ₂ CD ₂ O—, most preferably ¹¹ CH ₃ O—, ¹⁸ FCD ₂ O— or ¹⁸ FCD ₂ CD ₂ O—.

In the above formula, ring A is
(1) benzene,
(2) pyrazole,
(3) thiazole,
(4) piperidine, and (5) is selected from the group consisting tetrahydropyridine, the ring A, halogen, optionally substituted C _1-4 alkyl, optionally substituted C _1-4 alkoxy, substituted Optionally substituted C _7-14 aralkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, and optionally substituted cyclic group (provided that Expression

(P is 1 to 4) and may be substituted with 1 to 4 substituents selected from the group consisting of:

  The number of substituents is preferably 1 to 3, more preferably 1 or 2.

  When the number of substituents is 2 or more, the substituents on ring A may be bonded to form an optionally substituted ring. The “ring” of the “optionally substituted ring” includes a 5- to 6-membered heterocyclic ring containing one nitrogen atom or two oxygen atoms as a hetero atom.

  The “ring” may be substituted with one or more (preferably 1 to 5) substituents selected from the substituent group A.

In another embodiment of the present invention, the substituent of ring A is preferably, for example,
Halogen atoms [eg, iodine, bromine and fluorine],
Halogen _{atom, C 6-14} aryl and _{C 3-7} 1 to 3 amino optionally substituted with a substituent _{C 1-4} alkyl group selected from cycloalkyl [for example, trifluoromethyl and trifluoromethoxy Ethyl, cyclopropyl-methyl, cyclopropyl-ethyl, di-cyclopropyl-methyl, phenylethyl, isopropyl, isobutyl, cyclobutyl-methyl, cyclopropyl-butyl],
A _C2-4 alkenyl group [eg, propenyl],
A C _2-4 alkynyl group [eg, cyclopropylethynyl] optionally substituted by one C _3-7 cycloalkyl group,
C _1-4 alkoxy group optionally substituted with 1 to 3 substituents selected from a halogen atom and C _6-14 aryl [eg, methoxy group, difluoromethoxy group, trifluoromethoxy, difluoroethoxy, benzyl Oxy],
A C _3-7 cycloalkyl group [eg, cyclopropyl, cyclohexyl],
A C _7-14 aralkyl group [eg, benzyl],
A C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from a halogen atom and cyano [eg, fluorophenyl, difluorophenyl, cyanophenyl],
4- to 6-membered saturated heterocyclic group (preferably a 4- to 6-membered saturated heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, halogen atom, C _1-4 alkyl group and oxo May have 1 to 5 substituents selected from (provided that it may be substituted)

(Excluding cyclic groups represented by p is 1-4)) [Example, morpholinyl group, azetidinyl, tetrafluoropyrrolidinyl, difluoropiperidyl, dimethylmorpholinyl, oxaazabicyclooctyl, oxazepanyl piperidyl group, Tetrahydropyranyl, fluoroazetidinyl, difluoroazetidinyl, difluoropyrrolidinyl, oxo-oxazolidinyl, oxo-morpholinyl, tert-butyl-oxoimidazolidinyl, difluoromethyl-oxoimidazolidinyl, trifluoromethylpyrrolidinyl , Hydroxy-methylpiperidinyl, dimethyl-oxo-oxazolidinyl] and unsaturated heterocyclic groups (preferably 4 to 6 members having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur (preferably 5 to 5). 6-membered) unsaturated heterocycle 1-5 selected from a halogen atom, an optionally substituted C _1-4 alkoxy, an optionally substituted C _1-4 alkyl, hydroxy, a C _1-10 alkoxy-carbonyl group and cyano (E.g., thiazolyl, pyrazolyl, difluoropyrrolyl, chloropyridyl, cyanopyridyl, methoxypyrazolyl, cyclopropylmethoxy-pyrazolyl, trifluoroethoxy-pyrazolyl, dihydro-pyranyl, imidazolyl, dimethyl) Isoxazolyl, methylpyrazolyl, difluoromethylpyrazolyl, oxazolyl, pyridyl, difluoropyrrolyl, ethylformyl-hydroxy-pyrazolyl, hydroxy-pyrazolyl, difluoromethyl-oxo-dihydro-pyrazolyl, dihydro-pyrrolyl] It is.

Ring A is preferably, for example,
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) a halogen atom,
(2) an optionally substituted C _1-4 alkyl group,
(3) an optionally substituted C _1-4 alkoxy group,
(4) a C _3-7 cycloalkyl group,
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group ,
(6) a _C2-4 alkenyl group,
(7) C _7-14 aralkyl group,
(8) an optionally substituted C _6-14 aryl group, and (9) a halogen atom, a hydroxy group, an oxo group, a C _1-10 alkoxy-carbonyl group, an optionally substituted C _1-10 alkoxy group , And 0 or 1 oxygen atom as a hetero atom, optionally substituted with one or more substituents selected from an optionally substituted C _1-10 alkyl group, and 1 to 3 It may be substituted with 1 to 4 substituents selected from 4 to 6-membered heterocyclic groups containing a nitrogen atom.

Ring A is more preferably, for example,
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) a halogen atom (eg, fluorine, bromine, iodine),
(2) a C _1-4 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with 1 to 3 halogen atoms,
(3) C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy) optionally substituted with 1 to 3 halogen atoms,
(4) C _3-7 cycloalkyl group (eg, cyclopropyl),
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group (eg, cyclopropylethynyl),
(6) C _2-4 alkenyl group (eg, propenyl),
(7) C _7-14 aralkyl group (eg, benzyl),
(8) a C _6-14 aryl group (eg, fluorophenyl, difluorophenyl, cyanophenyl) optionally substituted with 1 to 4 substituents selected from a halogen atom and cyano, and (9) a halogen atom , hydroxy group, oxo _{group, C 1-10} alkoxy - is selected from the group, halogen substituted _{C 1-10} alkoxy group, and optionally substituted _{C 1-10} also be an alkyl group with halogen A 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms (eg, fluoroazeti) optionally substituted with 1 to 4 substituents Dinyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, trifluoromethyl-pyrrolidinyl, difluoropiperidinyl, hydroxy Cy-methyl-piperidinyl, oxo-1,3-oxazolidinyl, morpholinyl, oxo-morpholinyl, dihydropyranyl, tetrahydropyranyl, oxo-imidazolidinyl, methyl-oxo-imidazolidinyl, tert-butyl-oxo-imidazolidinyl, difluoromethyl-oxo -Imidazolidinyl, dihydro-1H-pyrrolyl, imidazolyl, thiazolyl, dimethyl-oxo-1,3-oxazolidinyl, dimethylisoxazolyl, difluoromethyl-oxo-2,5-dihydro-1H-pyrazolyl, pyrazolyl, methylpyrazolyl, chloro -1H-pyrazolyl, hydroxy-pyrazolyl, difluoromethoxy-pyrazolyl, ethoxycarbonyl-hydroxy-pyrazolyl, difluoropyrrolyl, difluoromethyl-pyra Lil, 1,3-oxazolyl, pyridyl, chloropyridyl, cyanopyridyl)
It may be substituted with 1 to 4 substituents selected from

In another aspect of the invention, ring A is more preferably, for example,
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) a halogen atom (eg, fluorine, bromine, iodine),
(2) a C _1-4 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with 1 to 3 halogen atoms,
(3) C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy) optionally substituted with 1 to 3 halogen atoms,
(4) C _3-7 cycloalkyl group (eg, cyclopropyl),
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group (eg, cyclopropylethynyl),
(6) C _2-4 alkenyl group (eg, propenyl),
(7) C _7-14 aralkyl group (eg, benzyl),
(8) a C _6-14 aryl group (eg, fluorophenyl, difluorophenyl, cyanophenyl) optionally substituted with 1 to 4 substituents selected from a halogen atom and cyano, and (9) a halogen atom , hydroxy group, oxo _{group, C 1-10} alkoxy - is selected from the group, halogen substituted _{C 1-10} alkoxy group, and optionally substituted _{C 1-10} also be an alkyl group with halogen A 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms (eg, fluoroazeti) optionally substituted with 1 to 4 substituents Dinyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, trifluoromethyl-pyrrolidinyl, difluoropiperidinyl, hydroxy Cy-methyl-piperidinyl, oxo-1,3-oxazolidinyl, oxo-morpholinyl, dihydropyranyl, tetrahydropyranyl, oxo-imidazolidinyl, methyl-oxo-imidazolidinyl, tert-butyl-oxo-imidazolidinyl, difluoromethyl-oxo-imidazolidinyl , Dihydro-1H-pyrrolyl, imidazolyl, thiazolyl, dimethyl-oxo-1,3-oxazolidinyl, dimethylisoxazolyl, difluoromethyl-oxo-2,5-dihydro-1H-pyrazolyl, pyrazolyl, methylpyrazolyl, chloro-1H -Pyrazolyl, hydroxy-pyrazolyl, difluoromethoxy-pyrazolyl, ethoxycarbonyl-hydroxy-pyrazolyl, difluoropyrrolyl, difluoromethyl-pyrazolyl, 1,3 Oxazolyl, pyridyl, chloropyridyl, cyanopyridyl)
It may be substituted with 1 to 4 substituents selected from

Ring A is more preferably, for example,
(1) a halogen atom (eg, fluorine, bromine, iodine),
(2) a C _1-4 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with 1 to 3 halogen atoms,
(3) C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy) optionally substituted with 1 to 3 halogen atoms,
(4) C _3-7 cycloalkyl group (eg, cyclopropyl),
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group (eg, cyclopropylethynyl),
(6) C _7-14 aralkyloxy group (eg, benzyloxy), and (7) a halogen atom, hydroxy group, oxo group, C _1-10 alkoxy-carbonyl group, C ₁ -optionally substituted with halogen 0 or 1 oxygen atom as a hetero atom, which may be substituted with 1 to 4 substituents selected from ₁₀ alkoxy groups, and C _1-10 alkyl groups optionally substituted with halogen; And a 4-6 membered heterocyclic group containing 1 to 3 nitrogen atoms (eg, fluoroazetidinyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, trifluoromethyl-pyrrolidinyl, difluoropi Peridinyl, hydroxy-methyl-piperidinyl, oxo-1,3-oxazolidinyl, oxo-morpholinyl, dihydropyranyl, teto Lahydropyranyl, oxo-imidazolidinyl, methyl-oxo-imidazolidinyl, tert-butyl-oxo-imidazolidinyl, difluoromethyl-oxo-imidazolidinyl, dihydro-1H-pyrrolyl, imidazolyl, dimethyl-oxo-1,3-oxazolidinyl, difluoromethyl-oxo- 2,5-dihydro-1H-pyrazolyl, pyrazolyl, methylpyrazolyl, chloro-1H-pyrazolyl, hydroxy-pyrazolyl, difluoromethoxy-pyrazolyl, ethoxycarbonyl-hydroxy-pyrazolyl, difluoropyrrolyl, difluoromethyl-pyrazolyl, 1,3- Oxazolyl, pyridyl)
A benzene ring optionally substituted with 1 to 4 substituents selected from
Particularly preferably,
(1) (a) 1 or 2 halogen atoms, or (b) 1 C _1-4 alkoxy group, and (2) a halogen atom, a hydroxy group, an oxo group, a C _1-10 alkoxy-carbonyl group, Optionally substituted with 1 to 4 substituents selected from a C _1-10 alkoxy group optionally substituted with halogen and a C _1-10 alkyl group optionally substituted with halogen; It is a benzene ring substituted with one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom as a telo atom and 1 to 3 nitrogen atoms.

  Most preferably, ring A has 0 or 1 oxygen atom as a hetero atom, and 1 to 3 nitrogen atoms, which may be substituted with 1 halogen atom and 1 to 4 halogen atoms. Is a benzene ring optionally substituted with one 4- to 6-membered heterocyclic group (eg, tetrahydropyranyl and difluoroazetidinyl).

  Here, the “one 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as a hetero atom” is preferably, for example, a morpholino group, a pyrrolyl group, A dihydropyrrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

In another aspect of the invention, ring A is more preferably, for example,
(I) piperidine, or (ii) tetrahydropyridine, wherein (i) or (ii) is
(1) C _2-4 alkenyl group (eg, propenyl),
(2) C _7-14 aralkyl group (eg, benzyl),
(3) a C _6-14 aryl group (eg, fluorophenyl, difluorophenyl, cyanophenyl) optionally substituted with 1 to 4 substituents selected from a halogen atom and cyano, and (4) a halogen atom , hydroxy group, oxo _{group, C 1-10} alkoxy - is selected from the group, halogen substituted _{C 1-10} alkoxy group, and optionally substituted _{C 1-10} also be an alkyl group with halogen A 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom as a hetero atom and 1 to 3 nitrogen atoms which may be substituted with 1 to 4 substituents (eg, thiazolyl, (Chloropyridyl, cyanopyridyl)
It may be substituted with 1 to 4 substituents selected from

In the above formula, R ² represents a substituent.

  As a substituent, the substituent selected from the said substituent A group is mentioned, for example.

Preferred examples of the substituent include, for example, a halogen atom, an optionally substituted alkyl group, and an optionally substituted C _6-14 aryl group, and more preferred examples include a halogen atom and a halogen. An alkyl group that may be used, and a C _6-14 aryl group, and more preferably an alkyl group (eg, methyl).

  In the above formula, m is 0-2. m is preferably 0 or 1, more preferably 0.

In the above formula, R ³ represents a substituent.

  As a substituent, the substituent selected from the said substituent A group is mentioned, for example.

The substituent is preferably, for example, a halogen atom, an optionally substituted C _1-10 alkyl group, an optionally substituted C _1-10 alkoxy group, and an optionally substituted C _7-16. An aralkyloxy group, and more preferably, for example, a halogen atom (eg, chlorine, fluorine), C _1-10 alkyl _optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms. A group (eg, methyl, isopropyl, isobutyl, trifluoromethyl), a C _1-10 alkoxy group (eg, methoxy, trifluoro) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms Methoxy) and a C _7-16 aralkyloxy group (eg, benzyloxy), and more preferably, for example, a halogen atom or an optionally substituted C _{1. -10} alkyl group, C _1-10 alkoxy group which may be substituted, and C _7-16 aralkyloxy group which may be substituted, and more preferably, for example, a halogen atom (eg, chlorine, fluorine) ), A C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl, trifluoromethyl) optionally substituted with 1 to 5 (preferably 1 to 3) halogen atoms, and 1 to 5 ( Preferable examples include C _1-10 alkoxy groups (eg, methoxy, trifluoromethoxy) optionally substituted with 1 to 3 halogen atoms, and particularly preferred examples include halogen atoms (eg, fluorine, chlorine). ).

  In said formula, n is 0-5. n is preferably 0 to 3, more preferably 0 or 1.

  In a preferred embodiment of the invention, both m and n are 0.

  As the compound represented by the formula (I), a compound represented by the formula (I ′) is preferable.

In the above formula, ring A ′ is
(I) benzene,
_1-4 substitutions selected from the group consisting of (ii) piperidine, and (iii) tetrahydropyridine, wherein the ring A ′ is selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy It may be substituted with a group.

Ring A ′ is preferably, for example,
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) halogen atom (preferably fluorine atom) and (2) C _1-4 alkoxy group (preferably methoxy)
It may be substituted with 1 to 4 substituents selected from

Ring A ′ is more preferably, for example,
(I) (1) a halogen atom (preferably a fluorine atom) and (2) a C _1-4 alkoxy group (preferably methoxy)
Benzene optionally substituted with 1 to 4 substituents selected from
(Ii) piperidine, or (iii) tetrahydropyridine,
More preferably, (i) benzene optionally substituted with a halogen atom (preferably a fluorine atom),
Particularly preferred is (i) benzene substituted with a halogen atom (preferably a fluorine atom).

  In the above formula, ring B is an optionally substituted cyclic group (however, an optionally substituted formula

(Wherein p is 1 to 4).

  The cyclic group represented by ring B preferably includes, for example, a 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms.

Ring B is preferably, for example,
(1) C _3-12 cycloalkyl which may be substituted,
(2) an optionally substituted dihydropyranyl,
(3) optionally substituted tetrahydropyranyl,
(4) optionally substituted azetidinyl,
(5) optionally substituted pyrrolidinyl,
(6) optionally substituted piperidinyl,
(7) optionally substituted imidazolyl,
(8) optionally substituted isoxazolyl,
(9) optionally substituted pyrazolyl,
(10) optionally substituted dihydropyrazolyl,
(11) optionally substituted pyridyl,
(12) optionally substituted pyrrolyl,
(13) an optionally substituted dihydropyrrolyl,
(14) optionally substituted phenyl,
(15) optionally substituted morpholinyl,
(16) an optionally substituted thiazolyl,
(17) optionally substituted oxazolidinyl,
(18) optionally substituted imidazolidinyl,
(19) selected from the group consisting of optionally substituted oxaazabicyclooctyl and (20) optionally substituted oxazepanyl, more preferably
It is selected from the group consisting of (1) optionally substituted tetrahydropyranyl and (2) optionally substituted azetidinyl.

In one embodiment of the present invention, the substituent for ring B is preferably, for example, a halogen atom (eg, fluorine, chlorine), a hydroxy group, a cyano group, an oxo group, a C _1-10 alkoxy-carbonyl group ( examples, ethoxycarbonyl), optionally _{C 1-10} alkoxy group (e.g. optionally substituted with halogen, difluoromethoxy), and which may _{C 1-10} alkyl group optionally (eg substituted by halogen, methyl, tert- butyl , Difluoromethyl, trifluoromethyl) to 1 to 4 substituents.

Ring B is more preferably, for example,
(1) dihydropyranyl,
(2) tetrahydropyranyl,
(3) azetidinyl,
(4) pyrrolidinyl,
(5) piperidinyl,
(6) imidazolyl,
(7) isoxazolyl,
(8) pyrazolyl,
(9) dihydropyrazolyl,
(10) pyridyl,
(11) pyrrolyl,
(12) dihydropyrrolyl,
(13) phenyl,
(14) morpholinyl,
(15) thiazolyl,
(16) oxazolidinyl, and (17) imidazolidinyl,
(Where (1) to (17) are substituted with a halogen atom (eg, fluorine, chlorine), a hydroxy group, a cyano group, an oxo group, a C _1-10 alkoxy-carbonyl group (eg, ethoxycarbonyl), or a halogen. Selected from an optionally substituted C _1-10 alkoxy group (eg, difluoromethoxy) and a C _1-10 alkyl group (eg, methyl, tert-butyl, difluoromethyl, trifluoromethyl) optionally substituted with halogen. Selected from the group consisting of optionally substituted with 1 to 4 substituents,
More preferably,
(1) tetrahydropyranyl, and (2) azetidinyl (where (1) or (2) is substituted with 1 to 4 substituents selected from a halogen atom (eg, fluorine) and an oxo group) Selected from the group consisting of:
Particularly preferably,
(1) tetrahydropyranyl, and (2) azetidinyl (wherein (1) or (2) may be substituted with 1 to 4 (preferably 2) halogen atoms (eg, fluorine)) Selected from the group consisting of

  Preferred examples such as substituents, moieties and rings described herein are more preferably used in combination.

Specific preferred examples of compound (I) include the following:
A compound of formula (I) wherein ring A is
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) a halogen atom,
(2) an optionally substituted C _1-4 alkyl group,
(3) an optionally substituted C _1-4 alkoxy group,
(4) a C _3-7 cycloalkyl group,
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group ,
(6) a _C2-4 alkenyl group,
(7) C _7-14 aralkyl group,
(8) an optionally substituted C _6-14 aryl group, and (9) a halogen atom, a hydroxy group, an oxo group, a C _1-10 alkoxy-carbonyl group, an optionally substituted C _1-10 alkoxy group , And 0 or 1 oxygen atom as a hetero atom, optionally substituted with one or more substituents selected from an optionally substituted C _1-10 alkyl group, and 1 to 3 Optionally substituted with 1 to 4 substituents selected from 4 to 6 membered heterocyclic groups containing nitrogen atoms;
R ¹ is, C _1-4 alkoxy group, a halogen atom and C _3-7 1 or more may be substituted with a substituent C _1-4 alkoxy group selected from cycloalkyl groups are the substituted _Optional C _1-4 alkoxy is radiolabeled;
R ² is a halogen atom, an optionally substituted C _1-10 alkyl group or an _optionally substituted C _6-14 aryl group;
R ³ is a halogen atom, an optionally substituted C _1-10 alkyl group or an optionally substituted C _1-10 alkoxy group;
m is 0 or 1; and n is 0-3. ]
Is preferred.

A compound of formula (I) wherein ring A is
(I) benzene,
(Ii) piperidine, or (iii) tetrahydropyridine, wherein (i) to (iii) are
(1) Halogen atom (eg, fluorine, bromine, iodine)
(2) a C _1-4 alkyl group (eg, methyl, trifluoromethyl) optionally substituted with 1 to 3 halogen atoms,
(3) C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy) optionally substituted with 1 to 3 halogen atoms,
(4) C _3-7 cycloalkyl group (eg, cyclopropyl),
(5) C _3-7 cycloalkyl-C _2-4 alkynyl group (eg, cyclopropylethynyl),
(6) C _2-4 alkenyl group (eg, propenyl),
(7) C _7-14 aralkyl group (eg, benzyl),
(8) a C _6-14 aryl group (eg, fluorophenyl, difluorophenyl, cyanophenyl) optionally substituted with 1 to 4 substituents selected from a halogen atom and cyano, and (9) a halogen atom , hydroxy group, oxo _{group, C 1-10} alkoxy - is selected from the group, halogen substituted _{C 1-10} alkoxy group, and optionally substituted _{C 1-10} also be an alkyl group with halogen A 4- to 6-membered heterocyclic group containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms (eg, fluoroazeti) optionally substituted with 1 to 4 substituents Dinyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, trifluoromethyl-pyrrolidinyl, difluoropiperidinyl, hydroxy Cy-methyl-piperidinyl, oxo-1,3-oxazolidinyl, morpholinyl, oxo-morpholinyl, dihydropyranyl, tetrahydropyranyl, oxo-imidazolidinyl, methyl-oxo-imidazolidinyl, tert-butyl-oxo-imidazolidinyl, difluoromethyl-oxo -Imidazolidinyl, dihydro-1H-pyrrolyl, imidazolyl, thiazolyl, dimethyl-oxo-1,3-oxazolidinyl, dimethylisoxazolyl, difluoromethyl-oxo-2,5-dihydro-1H-pyrazolyl, pyrazolyl, methylpyrazolyl, chloro -1H-pyrazolyl, hydroxy-pyrazolyl, difluoromethoxy-pyrazolyl, ethoxycarbonyl-hydroxy-pyrazolyl, difluoropyrrolyl, difluoromethyl-pyra Lil, 1,3-oxazolyl, pyridyl, chloropyridyl, cyanopyridyl)
Optionally substituted with 1 to 4 substituents selected from:
R ¹ represents a C _1-4 alkoxy group (eg, methoxy, ethoxy) which may be substituted with one or more substituents selected from a halogen atom, a C _1-4 alkoxy group and a C _3-7 cycloalkyl group. , Isopropoxy, cyclopropylmethoxy, difluoromethoxy, methoxyethoxy), and the optionally substituted C _1-4 alkoxy is radiolabeled;
R ² is a halogen atom, a C _1-10 alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1. ]
Is more preferable.

Specific preferred examples of compound (I ′) (compound (I ′) is included in compound (I)) include the following:
A compound of formula (I ′) wherein ring A ′ is
(1) halogen atom (preferably fluorine atom) and (2) C _1-4 alkoxy group (preferably methoxy)
(I) benzene, which may be substituted with 1 to 4 substituents selected from
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B, halogen atom (e.g., fluorine, chlorine), hydroxy group, cyano group, oxo _{group, C 1-10} alkoxy - carbonyl group (e.g., ethoxycarbonyl), optionally _{C 1-10} optionally substituted with halogen 1-4 substitutions selected from an alkoxy group (eg, difluoromethoxy) and a C _1-10 alkyl group (eg, methyl, tert-butyl, difluoromethyl, trifluoromethyl) optionally substituted with halogen Optionally substituted with a group,
(2) dihydropyranyl,
(3) tetrahydropyranyl,
(4) azetidinyl,
(5) pyrrolidinyl,
(6) piperidinyl,
(7) imidazolyl,
(8) isoxazolyl,
(9) pyrazolyl,
(10) dihydropyrazolyl,
(11) pyridyl,
(12) pyrrolyl,
(13) dihydropyrrolyl,
(14) phenyl,
(15) morpholinyl,
(16) thiazolyl,
(17) oxazolidinyl,
(18) imidazolidinyl,
(19) selected from the group consisting of oxaazabicyclooctyl and (20) oxazepanyl;
R ¹ is, C _1-4 alkoxy group, a halogen atom and C _3-7 1 or more may be substituted with a substituent C _1-4 alkoxy group selected from cycloalkyl groups are the substituted _Optional C _1-4 alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an optionally substituted C _1-10 alkyl group or an _optionally substituted C _6-14 aryl group;
R ³ is a halogen atom, an optionally substituted C _1-10 alkyl group or an optionally substituted C _1-10 alkoxy group;
m is 0 or 1; and n is 0-3. ]
Is preferred.

A compound of formula (I ′) wherein ring A ′ is
(I) (1) a halogen atom (preferably a fluorine atom) and (2) a C _1-4 alkoxy group (preferably methoxy)
Benzene substituted with 1 to 4 substituents selected from
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B may be substituted with 1 to 4 substituents selected from a halogen atom (eg, fluorine) and an oxo group.
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ represents a C _1-4 alkoxy group (eg, methoxy, ethoxy) which may be substituted with one or more substituents selected from a halogen atom, a C _1-4 alkoxy group and a C _3-7 cycloalkyl group. , Isopropoxy, cyclopropylmethoxy, difluoromethoxy, methoxyethoxy) and the C _1-4 alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an alkyl group which may be substituted with a halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1. ]
Is more preferable.

In another embodiment of the compounds of formula (I ′), ring A ′ is preferably, for example,
(I) (1) a halogen atom (preferably a fluorine atom) and (2) a C _1-4 alkoxy group (preferably methoxy)
Benzene substituted with 1 to 4 substituents selected from
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B may be substituted with 1 to 4 substituents selected from a halogen atom (eg, fluorine) and an oxo group.
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ represents ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O— (more preferably ¹¹ CH ₃ O—, ¹⁸ FCD ₂ O- or ^1
8 FCD ₂ CD ₂ O-, most preferably ¹¹ CH ₃ O-);
R ² is a halogen atom, an alkyl group which may be substituted with a halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1.
Is more preferable.

A compound of formula (I ′) wherein ring A ′ is
(I) benzene substituted with 1 to 4 halogen atoms (preferably fluorine atoms);
Ring B may be substituted with 1 to 4 (preferably 2) halogen atoms (eg, fluorine).
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ represents a C _1-4 alkoxy group (eg, methoxy, ethoxy) which may be substituted with one or more substituents selected from a halogen atom, a C _1-4 alkoxy group and a C _3-7 cycloalkyl group. , Isopropoxy, cyclopropylmethoxy, difluoromethoxy, methoxyethoxy) and the C _1-4 alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an alkyl group which may be substituted with a halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1. ]
Is more preferable.

In another embodiment of the compounds of formula (I ′), ring A ′ is preferably, for example,
(I) benzene substituted with 1 to 4 halogen atoms (preferably fluorine atoms);
Ring B is selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl optionally substituted with 1 to 4 (preferably 2) halogen atoms (eg, fluorine);
R ¹ represents ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O— (more preferably ¹¹ CH ₃ O—, ¹⁸ FCD ₂ O- or ^1
8 FCD ₂ CD ₂ O-, most preferably ¹¹ CH ₃ O-);
R ² is a halogen atom, an alkyl _optionally substituted with a halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1.

A compound of formula (I ′) wherein ring A ′ is
(I) benzene substituted with 1 to 4 halogen atoms (preferably fluorine atoms);
Ring B is selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl optionally substituted with 1 to 4 (preferably 2) halogen atoms (eg, fluorine);
R ¹ represents ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O— (more preferably ¹¹ CH ₃ O—, ¹⁸ FCD ₂ O- or ^1
8 FCD ₂ CD ₂ O-, most preferably ¹¹ CH ₃ O-);
R ² is a halogen atom, an alkyl _optionally substituted with a halogen, or a C _6-14 aryl group;
R ³ is a halogen atom (eg, chlorine, fluorine), a C _1-10 alkyl group (eg, methyl, isopropyl, isobutyl), or a C _1-10 alkoxy group (eg, methoxy);
m is 0 to 1; and n is 0 or 1. ]
Is particularly preferred.

Specifically, compound (I) is preferably
1- [2-fluoro-4- (tetrahydro -2H- pyran-4-yl) phenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine -4 (IH ) -One or a salt thereof;
1- [4- (3,3-difluoro-1-yl) -2-fluorophenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine -4 (1H) -one or a salt thereof;
5-([ ¹⁸ F] fluoro-methyloxy-d ₂ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole- 5-yl) pyridazin-4 (1H) -one or a salt thereof; and
5- (2- [ ¹⁸ F] fluoro-ethyloxy-d ₄ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole -5-yl) pyridazin-4 (1H) -one or a salt thereof.

  When compound (I) is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. And the like. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. And salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts), alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts), ammonium salts, etc. Is mentioned. On the other hand, when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid , Salts with organic acids such as maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.

  When compound (I) has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, any one of the isomers and the mixture are included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).

  Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.

  Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a co-crystal or a co-crystal salt means two or more kinds of unique solids each having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility and stability) at room temperature. Means a crystalline substance composed of The cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.

  Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I).

Compounds labeled with isotopes (eg, ² H (also expressed as D), ³ H (also expressed as T), ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.) Included in (I).

[Production method]
The compound of the present invention and the starting compound thereof can be produced by a method known per se, for example, by the method shown in the following scheme. Hereinafter, “room temperature” usually indicates 0 to 35 ° C. “Low temperature” usually indicates −78 to 0 ° C.

  Compound (I) can be obtained, for example, by the method described below or a method analogous thereto. The production method of compound (I) is shown by the reaction formulas 1 to 6 described in detail below or a method according thereto.

Each symbol of the compound in the reaction formula has the same meaning as described above. In the present specification, a methyl group (CH ₃ ) may be abbreviated as Me.

  In each of the following production methods, each raw material compound used for the production of compound (I) may form a salt. Examples of such salts include the same salts as the salt of compound (I).

  Moreover, each raw material compound used for manufacture of compound (I) can also be used for next reaction as a reaction mixture or a crude product. It can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, and chromatography. Can do. Examples of the solvent used for the recrystallization include water, alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, esters, sulfoxides, and organic acids. It is done. These solvents can be used alone, or two or more kinds of solvents may be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10. Moreover, when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.

In the substituent of the compound (I), a convertible functional group (eg, carboxyl group, amino group, hydroxyl group, carbonyl group, mercapto group, C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group) , C _7-16 aralkyloxy-carbonyl group, sulfo group, halogen atom, etc.), various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto.

  In the case of a carboxyl group, it can be converted by, for example, esterification, reduction, amidation, a conversion reaction to an optionally protected amino group, or the like.

  In the case of an amino group, it can be converted by a reaction such as amidation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like.

  In the case of a hydroxyl group, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation, and the like.

  In the case of a carbonyl group, it can be converted by a reaction such as reduction, oxidation, imination (including oximation and hydrazone formation), (thio) ketalization, alkylidene formation, thiocarbonylation, and the like.

  In the case of a mercapto group, it can be converted by a reaction such as alkylation or oxidation.

In the case of a C _1-6 alkoxy-carbonyl group, a C _6-14 aryloxy-carbonyl group, or a C _7-16 aralkyloxy-carbonyl group, it can be converted by a reaction such as reduction or hydrolysis.

  In the case of a sulfo group, it can be converted by a reaction such as sulfonamidation or reduction.

  In the case of a halogen atom, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions, and the like.

  In each of the above reactions, when the compound is obtained in a free state, it may be converted into a salt according to a conventional method. You can also.

  The conversion of these functional groups may be carried out according to a method known per se, for example, the method described in “Comprehensive Organic Transformations” (by Richard C. Larock) published in 1999 by Wiley-VCH.

  Moreover, in each reaction of the manufacturing method of the said compound (1) and each reaction of raw material compound synthesis, when the raw material compound has an amino group, a carboxyl group, a hydroxyl group, and a heterocyclic group as a substituent, peptide chemistry etc. are attached to these groups. In which a protecting group generally used is introduced, the target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the amino-protecting group include a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), each optionally having a substituent, a phenylcarbonyl group, C _1-6. Alkyl-oxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc.), allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group, fluorenylmethoxycarbonyl (Fmoc) group, C _{7- 10} aralkyl-carbonyl groups (eg, benzylcarbonyl, etc.), C _7-10 aralkyl-oxycarbonyl groups (eg, benzyloxycarbonyl (Z), etc.), C _7-10 aralkyl groups (eg, benzyl, etc.), 2- ( Trimethylsilyl) ethoxymethyl (SEM) group, trityl group, Taroiru groups and / or N, N-dimethylaminomethylene group, etc. are used. Examples of these substituents include phenyl groups, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl groups (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro groups, etc. Is used, and the number of substituents is about 1 to 3.

Examples of the protecting group for the carboxyl group include C _1-6 alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.) each optionally having a substituent, An allyl group, a benzyl group, a phenyl group, a trityl group and / or a trialkylsilyl group are used. Examples of these substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), formyl groups, C _1-6 alkyl-carbonyl groups (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), nitro groups, and the like. The number of substituents used is about 1-3.

Examples of the hydroxyl-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), which each may have a substituent, C _7-10 aralkyl group (eg, benzyl etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl etc.), benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl etc.) ), Tetrahydropyranyl group, furanyl group and / or silyl group. Examples of these substituents include halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl groups (eg, methyl, ethyl, n-propyl, etc.), phenyl groups, C _7-10 aralkyl groups. (Eg, benzyl, etc.), C _1-6 alkoxy groups (eg, methoxy, ethoxy, n-propoxy, etc.), nitro groups and the like are used, and the number of substituents is about 1 to 4.

Introduction or removal of these protecting groups, a method known per se, for example, Wiley-Interscience, Inc. 1999 annual ^{"Protective Groups in Organic Synthesis, 3 rd} Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to And so on.

  When compound (I) exists as a configurational isomer, diastereomer, conformer, etc., each can be isolated by a known means. In addition, when compound (1) is an optically active substance, the racemate can be separated into a (+) isomer and a (−) isomer by an ordinary optical resolution means.

  When compound (I) contains optical isomers, stereoisomers, positional isomers, rotational isomers, and tautomers, these are also included as compound (I), and synthetic methods known per se Each can be obtained as a single product by the separation method.

  For example, as the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.

  1) Fractional recrystallization method: racemate and optically active compound (eg, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine) , (−)-1-phenethylamine, cinchonine, (−)-cinchonidine, brucine, etc.), and this is separated by fractional recrystallization. If desired, a free optical isomer can be obtained through a neutralization step. How to get.

  2) Chiral column method: A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENALTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphorus The optical isomers are separated by developing the solution as an acid buffer solution) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution. Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

  3) Diastereomer method: A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this is subjected to ordinary separation means (eg, fractional recrystallization method, chromatography method, etc.). A method of obtaining an optical isomer by separating an optically active reagent site by chemical treatment such as hydrolysis after making a single substance. For example, when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid ], (-)-Methoxyacetic acid, etc.) are subjected to a condensation reaction to give ester or amide diastereomers, respectively. On the other hand, when compound (I) has a carboxyl group, an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

  The salt of compound (I) is in accordance with a method known per se, for example, when compound (I) is a basic compound, by adding an inorganic acid or an organic acid, or compound (I) is an acidic compound In some cases, it can be produced by adding an organic base or an inorganic base.

  The solvent, acid, and base used in the method for producing the compound of the present invention will be described below.

  As the “alcohols”, for example, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol and the like are used.

  Examples of the “ethers” include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.

  Examples of “hydrocarbons” include benzene, toluene, cyclohexane, hexane, and the like.

  Examples of the “amides” include N, N-dimethylformamide, dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine, hexamethylphosphoric triamide and the like.

  Examples of the “halogenated hydrocarbons” include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and the like.

  As the “nitriles”, for example, acetonitrile, propionitrile and the like are used.

  As the “ketones”, for example, acetone, ethyl methyl ketone and the like are used.

  As the “esters”, for example, ethyl acetate or the like is used.

  As the “sulfoxides”, for example, dimethyl sulfoxide and the like are used.

  Examples of the “organic acids” include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

  Examples of “mineral acids” include hydrochloric acid, sulfuric acid and the like.

  Examples of “Lewis acids” include boron trichloride, boron tribromide, and the like.

  Examples of the “inorganic bases” include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like.

  Examples of the “basic salts” include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, ammonium acetate and the like.

  As the “aromatic amines”, for example, pyridine, lutidine and the like are used.

  Examples of “tertiary amines” include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine. N-methylmorpholine, 1,8-diazabicyclo [5,4,0] undec-7-ene and the like are used.

  As the “alkali metal hydrides”, for example, sodium hydride, potassium hydride and the like are used.

  As the “alkali metals”, for example, sodium, lithium, potassium and the like are used.

  Examples of the “metal amides” include sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.

  As the “alkyl metals”, for example, butyl lithium, sec-butyl lithium, tert-butyl lithium and the like are used.

  As the “aryl metals”, for example, phenyl lithium and the like are used.

  As the “metal alkoxides”, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like are used.

Reaction formula 1

[Wherein R ^{1 ′} is a radiolabeled C _1-4 alkyl group which may be substituted, L represents a leaving group, and other symbols are as defined above. ]

Examples of the leaving group represented by L include a halogen atom (eg, chlorine, bromine, iodine), a halogenated C _1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy). , Trifluoromethylsulfonyloxy), a C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy, p-toluenesulfonyloxy) _optionally substituted with a C _1-6 alkyl group, a methanesulfonyl group, and the like. Preferably a halogen atom or an optionally halogenated C _1-6 alkylsulfonyloxy group.

  Compound (1) can be produced by a method known per se or a method analogous thereto, the method shown in the following reaction formulas 2 to 5 or a method analogous thereto. Compound (1) includes compound (1a), compound (1b) and compound (1c).

  Compound (2) can be produced by a method known per se or a method analogous thereto, the method shown in the following Reaction Scheme 6 or a method analogous thereto.

  Compound (4) can be obtained by a method known per se, for example, App. Radiat. Isot, 2009, 67 (1), 106-110, Bioorganic & Medicinal Chemistry, 2005, 13, 1811-1818, App. Radit. , 57 (1), 335-342, or Journal of Fluorine Chemistry, 2004, 125, 1879-1886, or a method analogous thereto.

  In step 1, compound (1) is reacted with trimethylsilyl chloride in the presence of sodium iodide to give compound (3). Sodium iodide is used in an amount of about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (1). Trimethylsilyl chloride is also used in an amount of about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (1). The solvent is not particularly limited as long as the reaction proceeds. For example, nitriles are preferable. The reaction temperature is usually room temperature to 200 ° C, preferably 80 ° C. The reaction time is usually 1 to 20 hours, preferably 3 to 10 hours.

  In step 2, compound (2) is reacted with palladium carbon in an acid or hydrogen atmosphere to obtain compound (3).

  When reacting with an acid, the acid is not particularly limited as long as the reaction proceeds. For example, acetic acid containing hydrogen bromide or trifluoroacetic acid is preferable. The reaction temperature is usually room temperature to 200 ° C, preferably 50 ° C to 100 ° C. The reaction time is usually 1 to 20 hours, preferably 3 to 12 hours.

  When making it react with palladium carbon, palladium carbon is used about 0.01-5 mol with respect to 1 mol of compound (2), Preferably 0.05-0.3 mol is used. The solvent is not particularly limited as long as the reaction proceeds. For example, alcohols are preferable. The reaction temperature is usually 0 ° C to 150 ° C, preferably room temperature. The reaction time is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours.

  In step 3, compound (I) is obtained by reacting compound (3) with compound (4). Usually, an excessive amount of compound (3) may be used relative to compound (4), but the required amount is not particularly limited as long as the reaction proceeds. The reaction in this step can be carried out in the presence of a base if desired. The solvent is not particularly limited as long as the reaction proceeds. For example, acetone is preferable. The reaction temperature is usually 0 ° C to 150 ° C, preferably room temperature. The reaction time is usually 10 seconds to 2 hours, preferably 30 seconds to 20 minutes.

Alternatively, compound (I) can also be obtained using the method described below.
Compound (I) represents compound (3) in the presence of a base such as NaH in the presence of L- (CH ₂ ) _n -L or L- (CD ₂ ) _n -L (n: And can be synthesized by reacting the resulting compound with a nucleophile such as an ¹⁸ F anion.
The amount of L- (CH ₂ ) _n -L or L- (CD ₂ ) _n -L and NaH is not particularly limited, but is usually 1 to 10 moles per 1 mole of compound (3). The reaction solvent is not particularly limited as long as the reaction proceeds. For example, halogenated hydrocarbons, amides, sulfoxides, ethers, nitriles, esters, hydrocarbons, water and other solvents, and mixtures thereof A solvent or the like is preferable.
While the reaction time varies depending on the reagent and solvent used, it is generally 0.1-24 hours, preferably 0.5-12 hours.
The reaction temperature is generally 0-200 ° C, preferably 0-100 ° C.
A nucleophilic agent such as ¹⁸ F anion is used in excess with respect to 1 mol of the alkylated compound (3).
The reaction in this step can be carried out in the presence of a base if desired. The reaction solvent is not particularly limited as long as the reaction proceeds. For example, acetonitrile, dimethyl sulfoxide and N, N-dimethylformamide are preferable. The reaction temperature is usually 0 to 150 ° C., preferably room temperature. The reaction time is usually 10 seconds to 2 hours, preferably 30 seconds to 20 minutes.

Reaction formula 2

  Compound (5) can be produced according to a method known per se or a method analogous thereto. Moreover, it can also obtain as a commercial item.

  Compound (7) can be produced according to a method known per se or a method analogous thereto. Moreover, it can also obtain as a commercial item.

  Compound (14) can be produced according to a method known per se or a method analogous thereto. Moreover, it can also obtain as a commercial item.

  In step 4, compound (5) is reacted with sodium nitrite to give compound (6), which can be carried out in the presence of an acid if desired. The acid is preferably, for example, hydrochloric acid or sulfuric acid. Sodium nitrite is used in an amount of about 1-10 mol, preferably 1-3 mol, per 1 mol of compound (5). The solvent is not particularly limited as long as the reaction proceeds. For example, water is preferable. The reaction temperature is usually −78 ° C. to room temperature, preferably 0 ° C. The reaction time is usually 30 seconds to 5 hours, preferably 30 minutes to 1 hour.

  In step 5, compound (7), compound (17) or compound (33) is reacted with compound (6) to give compound (8), compound (18) or compound (34), respectively. This reaction can be carried out in the presence of a base if desired. Compound (7), Compound (17) or Compound (33) is used in an amount of about 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (6). The solvent is not particularly limited as long as the reaction proceeds. For example, a mixed solvent of water and methanol is preferable. The reaction temperature is usually −78 ° C. to room temperature, preferably 0 ° C. The reaction time is usually 1 to 24 hours, preferably 3 to 15 hours.

  In step 6, compound (8), compound (18) or compound (34) is reacted with N, N-dimethylformamide dimethyl acetal to obtain compound (9), compound (1) or compound (35), respectively. . N, N-dimethylformamide dimethyl acetal is used in an amount of about 1 to 30 mol, preferably 1 to 3 mol, per 1 mol of compound (8), compound (18) or compound (34). The solvent is not particularly limited as long as the reaction proceeds, and can be carried out without a solvent. For example, DMF is preferred. The reaction temperature is usually room temperature to 200 ° C, preferably 100 to 150 ° C. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

  In step 7, compound (9) is reacted with a base to give compound (10). The base is preferably an aqueous sodium hydroxide solution, for example. The sodium hydroxide aqueous solution is used in an amount of about 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (9). The solvent is not particularly limited as long as the reaction proceeds. For example, ethanol is preferable. The reaction temperature is usually from 0 ° C to 100 ° C, preferably room temperature. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

  In step 8, compound (10) is reacted with N, O-dimethylhydroxylamine in the presence of a condensing agent and an activator to give compound (11). The condensing agent is preferably, for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The activator is preferably 1-hydroxybenzotriazole, for example. The condensing agent is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (10). The activator is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (10). N, O-dimethylhydroxylamine is used in an amount of about 1 to 3 mol, preferably 1 to 2 mol, per 1 mol of compound (10). The solvent is not particularly limited as long as the reaction proceeds. For example, DMF is preferable. The reaction temperature is usually from 0 ° C to 100 ° C, preferably room temperature. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

  In step 9, compound (12) is obtained by reacting compound (11) with methylmagnesium bromide or methyllithium. Methyl magnesium bromide is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (11). The solvent is not particularly limited as long as the reaction proceeds. For example, THF and diethyl ether are preferable. The reaction temperature is usually -78 ° C to room temperature, preferably -78 ° C. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

  In step 10, compound (12) is reacted with N, N-dimethylformamide dimethyl acetal to obtain compound (13). N, N-dimethylformamide dimethyl acetal is used in an amount of about 1-30 mol, preferably 1-3 mol, per 1 mol of compound (12). The solvent is not particularly limited as long as the reaction proceeds, and can be carried out without a solvent. For example, DMF is preferred. The reaction temperature is usually room temperature to 200 ° C, preferably 100 to 150 ° C. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

  In step 11, compound (13) or compound (35) is reacted with compound (14) to obtain compound (1) or compound (2), respectively. If desired, this reaction can be carried out in the presence of an acid. Examples of the acid include acetic acid and trifluoroacetic acid. Compound (14) is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (13) or compound (35). The solvent is not particularly limited as long as the reaction proceeds, but for example, acetic acid, ethanol and the like are preferable. The reaction temperature is usually −20 ° C. to 100 ° C., preferably room temperature. The reaction time is usually 1 to 24 hours, preferably 1 to 15 hours.

Reaction formula 3

  Compound (15) can be produced according to a method known per se or a method analogous thereto. Moreover, it can also obtain as a commercial item.

  In step 12, an organolithium compound prepared from compound (15) and n-butyllithium is reacted with glycidyl methyl ether to obtain compound (16). n-Butyllithium is used in an amount of about 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (15). Glycidyl methyl ether is used in an amount of about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (15). The solvent is not particularly limited as long as the reaction proceeds. For example, THF is preferable. In the preparation of the organolithium compound, the reaction temperature is usually -78 ° C to 0 ° C, preferably -78 ° C. In the reaction with glycidyl methyl ether, the reaction temperature is usually -78 ° C to 50 ° C, preferably room temperature. The reaction time is usually 10 minutes to 5 hours in all steps, preferably 30 minutes to 1 hour.

  In step 13, compound (16) is reacted with an oxidant prepared from DMSO and trifluoroacetic anhydride to obtain compound (17). DMSO is used in an amount of about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (16). Trifluoroacetic anhydride is used in an amount of about 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of compound (16). The solvent is not particularly limited as long as the reaction proceeds. For example, THF is preferable. The reaction temperature is usually −78 ° C. to room temperature, preferably 0 ° C. The reaction time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

Reaction formula 4

[Wherein, R ⁴ represents an alkyl group or an aryl group, L represents a leaving group, and other symbols are as defined above. ]

  Compound (19) can be produced according to a method known per se or a method analogous thereto.

  Compound (21) can be produced according to a method known per se or a method analogous thereto.

  Compound (24) can be produced according to a method known per se or a method analogous thereto. Moreover, it can also obtain as a commercial item.

  In Step 14, compound (19) is reacted with benzyl bromide to obtain compound (20). This reaction can be carried out in the presence of a base if desired. Benzyl bromide is used in an amount of about 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (19). The solvent is not particularly limited as long as the reaction proceeds. For example, DMF is preferable. The reaction temperature is usually 0 ° C. to 50 ° C., preferably room temperature. The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 25 hours.

  In step 15, compound (20) and compound (21) are subjected to a coupling reaction in the presence of a palladium catalyst to obtain compound (22). The palladium catalyst is preferably, for example, PdCl2 {Pt-Bu2 (Ph-p-NMe2)} 2. This reaction can be carried out in the presence of a base if desired. Compound (21) is used in an amount of about 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of compound (20). The palladium catalyst is used in an amount of about 0.0001 to 2 mol, preferably 0.001 to 0.5 mol, per 1 mol of compound (20). The solvent is not particularly limited as long as the reaction proceeds. For example, toluene is preferable. The reaction temperature is usually room temperature to 200 ° C, preferably 100 ° C to 120 ° C. The reaction time is usually 1 hour to 48 hours, preferably 3 hours to 25 hours.

  In Step 16, compound (22) is reacted with palladium carbon under a hydrogen atmosphere to obtain compound (23). Palladium carbon is used in an amount of about 0.01 to 5 mol, preferably 0.05 to 0.5 mol, per 1 mol of compound (22). The solvent is not particularly limited as long as the reaction proceeds. For example, alcohols are preferable. The reaction temperature is usually from 0 ° C to 100 ° C, preferably room temperature. The reaction time is usually 10 minutes to 72 hours, preferably 1 hour to 60 hours.

  In Step 17, compound (1a) is obtained by reacting compound (23) with compound (24). This reaction can be carried out in the presence of a base if desired. Compound (24) is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (23). The solvent is not particularly limited as long as the reaction proceeds. For example, DMF is preferable. The reaction temperature is usually from room temperature to 200 ° C, preferably 150 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.

Reaction formula 5

[Wherein, R ⁵ represents an alkyl group or an aryl group, L represents a leaving group, and other symbols are as defined above. ]

  Compound (25) can be produced according to scheme 1 or scheme 2, or a method analogous thereto.

  Compound (29) can be obtained as a commercial product, and can also be produced according to a method known per se or a method analogous thereto.

  In step 18, compound (25) is reacted with allyl bromide to give compound (26). Allyl bromide is used in an amount of about 1-5 mol, preferably 1-3 mol, per 1 mol of compound (25). The solvent is not particularly limited as long as the reaction proceeds. For example, acetonitrile is preferable. The reaction temperature is usually from room temperature to 150 ° C, preferably 80 ° C. The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 4 hours.

  In step 19, compound (26) or compound (30) is reacted with sodium borohydride or the like to produce compound (27) or compound (31). Sodium borohydride is used in an amount of about 1-10 mol, preferably 1-5 mol, per 1 mol of compound (26) or compound (30). The solvent is not particularly limited as long as the reaction proceeds. For example, methanol is preferable. The reaction temperature is usually −20 ° C. to 80 ° C., preferably room temperature. The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.

  In step 20, compound (27) is reacted with 1,3-dimethylbarbituric acid in the presence of a palladium catalyst to obtain compound (28). An example of the palladium catalyst is tetrakistriphenylphosphine palladium. 1,3-dimethylbarbituric acid is used in an amount of about 1-10 mol, preferably 1-3 mol, per 1 mol of compound (27). The solvent is not particularly limited as long as the reaction proceeds. For example, toluene is preferable. The reaction temperature is usually from room temperature to 200 ° C, preferably 120 ° C. The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.

  In step 21, compound (28) or compound (32) is reacted with compound (29) to give compound (1b) or compound (1c). This reaction can be carried out in the presence of a base if desired. Compound (29) is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (28) or compound (32). The solvent is not particularly limited as long as the reaction proceeds. For example, THF is preferable. The reaction temperature is usually −20 ° C. to 150 ° C., preferably room temperature. The reaction time is usually 1 hour to 24 hours, preferably 1 hour to 12 hours.

  In step 22, compound (25) is reacted with benzyl bromide to give compound (30). The benzyl bromide is used in an amount of about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (25). The solvent is not particularly limited as long as the reaction proceeds. For example, acetonitrile is preferable. The reaction temperature is usually from room temperature to 150 ° C, preferably 80 ° C. The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 4 hours.

  Step 23 is a method for producing the compound (32) by reacting the compound (31) with palladium hydroxide carbon or the like in a hydrogen atmosphere. Palladium hydroxide carbon is used in an amount of about 0.01 to 5 mol, preferably 0.05 to 1 mol, per 1 mol of compound (31). The solvent is not particularly limited as long as the reaction proceeds. For example, methanol is preferable. The reaction temperature is usually room temperature to 100 ° C, preferably 50 ° C. The reaction time is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.

Reaction formula 6

  Compound (33) can be produced according to a method known per se or a method analogous thereto.

  The compound (I) of the present invention obtained by the above method can be purified by chromatography. In addition, the compounds (1), (2) and (3) can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.

  In any of the above-described production methods or processes, a known protection and deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, or substituent exchange may be performed as desired. Compound (I) can be synthesized by using the reaction alone or in combination of two or more thereof.

  Similar to compound (I), a prodrug of compound (I) can be used. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, or hydrolyzed to compound (I). A compound that changes, and a compound that undergoes hydrolysis by gastric acid and changes to compound (I).

  Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compounds in which the xy group is esterified or amidated (for example, the carboxy group of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.); Is mentioned. These compounds can be produced from compound (I) by a known method. The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.

  In one aspect, the compounds of the invention may be labeled as radioactive tracers for in vitro imaging. In another aspect, the compounds of the invention may be prepared as positron emission tomography (PET) tracers for in vivo imaging and quantification of PDE10A.

Suitable nuclides that may be introduced into the compound include ³ H (also described as T), ¹¹ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, ⁸² Br, ¹²³ I, ¹³¹ I, ⁷⁵ Br, ¹⁵ O, Examples include, but are not limited to, ¹³ N, ²¹¹ At or ⁷⁷ Br. The nuclide introduced into the present radiolabeled compound depends on the specific analytical use or pharmaceutical use of the radiolabeled compound.

Thus, compounds that introduce ³ H, ³⁵ S, ¹²⁵ I, or ⁸² Br are generally most useful for in vitro imaging and competition assays of PDE10. For PET tracers, compounds that introduce nuclides selected from ¹¹ C, ¹⁸ F, ¹²³ I, ¹³¹ I, ⁷⁵ Br or ⁷⁷ Br are preferred. For some applications, the introduction of chelate nuclides such as Tc ^99m is also useful. In other applications, ¹⁸ F has a longer half-life, so imaging can be performed long enough to generate a more specific signal and improve conditions for receptor quantification studies. In some cases, ¹⁸ F is preferred over ¹¹ C. The compounds can be radiolabeled with either positrons or gamma-ray radionuclides.

  When labeled with the appropriate nuclide, radiolabeled PDE10A inhibitors are highly useful for a variety of in vitro and / or in vivo imaging applications. Specific examples of possible imaging applications include measuring the location of PDE10A, relative activity and / or quantification, radioimmunoassay of PDE10A inhibitors, and measuring the distribution of PDE10A in a mammal or its organ or tissue sample Include, but are not limited to, autoradiography. By using a radioactive tracer labeled with fluorine-18 or carbon-11 that gives PDE10A specific images in the brain and other tissues, the dose required to effectively inhibit the PDE10A enzyme is Can be determined from images of inhibition by PET radiotracers at

In a particular embodiment, the radiolabeled PDE10A inhibitor, when labeled with positron emitting nuclides such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, of PDE10A in the brains of living human and laboratory animals. Useful for positron emission tomography (PET) imaging. These radiolabeled PDE10A inhibitors interact with unlabeled PDE10A inhibitors and PDE10A in vivo by competition between unlabeled drug and radiolabeled compound for binding to the receptor. May be used as a research tool to study This type of quantitative study was performed to determine the relationship between PDE10A occupancy and the dose of unlabeled PDE10A inhibitor, and by varying doses of unlabeled PDE10A antagonists, agonists and inverse agonists. Useful for studying periods of body blockade. As a clinical tool, a radiolabeled PDE10A inhibitor may be used to help define a clinically effective dose of the PDE10A inhibitor. In animal experiments, radiolabeled PDE10A inhibitors can be used to provide useful information for selection among potential drug candidates for selection for clinical development. . Radiolabeled PDE10A inhibitors may also be used to study the local distribution and concentration of PDE10A in living human brains and living laboratory animal brains, and tissue samples. Radiolabeled PDE10A inhibitors may also be used to study disease or pharmaceutically relevant changes in PDE10A concentrations.

  In particular aspects of the present invention, PET tracers such as the present radiolabeled PDE10A inhibitors and currently available PET technology can be used to obtain (but not limited to) the following information. Relationship between receptor occupancy by PDE10A inhibitor candidates and clinical efficacy in patients; dose selection for clinical trials of PDE10A inhibitors before beginning long-term clinical studies; comparative efficacy of structurally novel PDE10A inhibitors Investigating the effects of PDE10A inhibitors on transporter affinity and density in vivo during treatment of clinical subjects with PDE10A inhibitors and other drugs; for example, 1) during the active phase of psychosis or mental condition; 2) Changes in density and distribution of PDE10A for evaluation of efficacy during therapy, or 3) Changes in PDE10A expression and distribution in CNS disorders; Imaging of neurodegenerative diseases when PDE10A is elevated Imaging of neurodegenerative diseases when PDE10A is involved;

  Isotopically labeled compounds of formula (I) are generally appropriately isotopically substituted for the unlabeled reagent used previously to produce the radiolabeled derivative. Labeled reagents can be used to produce by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples.

  The radiolabeled PDE10A inhibitors of the present invention have utility in imaging PDE10A or in diagnostic imaging for any of the described neurological and psychiatric disorders associated with PDE10A dysfunction.

  The present invention is also a method for quantitatively imaging PDE10A in mammals, wherein an effective amount of a radiolabeled compound of the present invention is administered to a mammal in need of such quantitative imaging. Relates to a method comprising:

  The present invention also relates to a method for quantitatively imaging a tissue having PDE10A in a mammal, wherein an effective amount of the radiolabeled compound of the present invention is applied to such a mammal that needs to be quantitatively imaged. To a method comprising administering.

  The present invention is also a method for quantitatively imaging PDE10A in tissues of mammalian species, wherein an effective amount of the radiolabeled compound of the present invention is applied to such mammalian species that need to be quantitatively imaged. Is administered.

  The present invention is also a method for quantitatively imaging PDE10A in the mammalian brain, wherein an effective amount of the radiolabeled compound of the present invention is administered to such a mammal that needs to be quantitatively imaged. To a method comprising:

  Furthermore, the present invention provides a method for detecting or quantifying PDE10A in mammalian tissue, comprising administering an effective amount of a radiolabeled compound of the present invention to a mammal in which such quantification is desired. About.

  In a particular embodiment of the method of the present invention, the mammal is a human.

The radiolabeled compound of the present invention can be used for imaging of PDE10A or diagnostic images for the following diseases and symptoms in mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice, rats, etc.). It is useful for conversion.
Psychotic disorders (eg, short-term psychotic disorders, shared psychotic disorders);
Psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine;
Delusional disorder;
Anxiety disorder;
Movement disorders;
Mood disorders;
Major depressive disorder;
Mixed major depressive disorder with psychotic disorders including delusional disorder or schizophrenia;
Mild, moderate or severe types of major depression episodes;
Manic or mixed mood episode;
Hypomanic mood episode;
Depressive episodes with atypical features;
Depressive episode with melancholic features;
Depressive episodes with catatonic characteristics;
Mood episodes that occur after childbirth;
Post-stroke depression;
Mood disorders;
Mild depressive disorder;
autism;
Drug addiction;
Neurodegenerative disorders;
Neurodegeneration associated with brain trauma;
Neurodegeneration associated with stroke;
Neurodegeneration associated with cerebral infarction;
Neurodegeneration associated with hypoglycemia-induced neurodegenerative epileptic seizures;
Neurodegeneration associated with neurological poisoning;
Multiple system atrophy;
Alzheimer's disease;
dementia;
Multiple infarct dementia;
Alcoholic dementia or other drug-related dementia;
Dementia associated with intracranial tumors or brain trauma;
Dementia associated with Huntington's disease or Parkinson's disease;
AIDS-related dementia;
Frontotemporal dementia;
Delirium;
Amnestic disorder;
Post-traumatic stress disorder;
Mental retardation;
Learning disabilities (eg, reading disabilities, mathematical disabilities, or written disabilities);
Attention deficit / hyperactivity disorder;
Age-related cognitive decline;
Premenstrual dysphoric disorder;
Postpsychiatric depressive disorder with schizophrenia;
Bipolar disorder including bipolar I disorder, bipolar II disorder;
Mood circulatory disorder;
Parkinson's disease;
Huntington's disease;
Delusions;
Schizophrenia (eg, delusional schizophrenia, demolished schizophrenia, demolished schizophrenia, tension schizophrenia, undifferentiated schizophrenia, remnant schizophrenia);
Schizophrenia-like disorder;
Delusional or depressive schizophrenia disorder;
Delusional personality disorder;
Schizophrenic personality disorder;
Obesity;
metabolic syndrome;
Non-insulin dependent diabetes mellitus (NIDDM);
Impaired glucose tolerance.

  Among them, the radiolabeled compound of the present invention is useful for imaging of PDE10A or diagnostic imaging for schizophrenia in humans.

  The compound of the present invention can be used as it is or according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia), a normal non-toxic pharmaceutically acceptable carrier suitable for each route of administration, Dosage forms prepared alone or together with suitable dosage unit formulations containing agents and excipients, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets), pills, Powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules) ), Aerosol, film (eg, orally disintegrating film, oral mucosa film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, ICV, intracapsular injection {Nothing} , Drops, implants, transdermal preparations, ointments, lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), inhalation Oral or parenteral (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, nasal, vagina, etc.) , Rectal, sublingual, direct lesion administration).

  Here, as the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as a raw material for preparations are used. Excipients, lubricants, binders, disintegrants in solid preparations; dissolution aids in liquid preparations It is formulated as an agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

  Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.

  Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

  Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.

  Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

  Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

  Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.

  Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.

  Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

  Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.

  A preferred example of the soothing agent is benzyl alcohol.

  Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

  Preferable examples of the antioxidant include sulfite and ascorbate.

  Suitable examples of colorants include water-soluble edible tar pigments (eg, edible pigments such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, etc.), water Insoluble lake pigments (eg, aluminum salts of the above water-soluble edible tar pigments) and natural pigments (eg, β-carotene, chlorophyll, bengara).

  Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

  The pharmaceutical composition of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia. Below, the specific manufacturing method of a formulation is explained in full detail.

  The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dose of the compound of the present invention, etc., for example, about 0.01 to 100% by weight, preferably Is 0.1 to 95% by weight.

  The compounds are used as single active agents or in the treatment of psychosis, in particular schizophrenia and bipolar disorder, obsessive compulsive disorder, major depression, Parkinson's disease, Alzheimer's disease, cognitive dysfunction and / or memory loss Other agents such as nicotinic α7 agonists, nicotinic α7 partial agonists, nicotinic α7 positive allosteric modulators, PDE2 inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, calcium channel blockers, muscarinic m1 and m2 modulator, adenosine receptor modulator, ampakines, glycine transporter 1 inhibitor, NMDA-R modulator, mGluR modulator, dopamine modulator, serotonin modulator, selective serotonin reuptake inhibitor, serotonin nore In combination with other drugs such as nephrin reuptake inhibitors, norepinephrine dopamine reuptake inhibitors, triple reuptake inhibitors, cannabinoid modulators, and cholinesterase inhibitors (eg, donepezil, rivastigmine, and galantamine) Can be administered. In such combinations, each active ingredient can be administered according to either their normal dosage range or a dosage lower than their normal dosage range, administered either simultaneously or sequentially. be able to.

  Suitable drugs for use in combination with the compounds of the present invention include other suitable schizophrenia drugs such as haloperidol, clozapine, olanzapine, risperidone, aripiprazole, ziprasidone, paliperidone, quetiapine fumarate, lurasidone HCl (Lurasidone HCl ) And PDE10A inhibitors; including but not limited to bipolar disorder drugs such as lithium, olanzapine, aripiprazole and valproic acid; Parkinson's disease drugs such as levodopa, bromocriptine, Examples include, but are not limited to, pergolide, pramipexole, tolcapone, procyclidine, trihexyphenidyl and benztropine; drugs used to treat major depression, such as amitriptyline, protriptyline, de Drugs, such as galantamine, tacrine, donepezil, rivastigmine, including but not limited to, pramine, nortriptyline, paroxetine, fluoxetine, sertraline, bupropion, escitalopram, mirtazapine, venlafaxine, duloxetine , Memantine, neotropin, selegiline, estrogen and iodoquinol; drugs used to treat dementia, such as thioridazine, haloperidol, risperidone, tacrine, donepezil, and rivastigmine But not limited to; drugs used to treat epilepsy such as phenytoin, phenobarbital, carbamazepine, valproic acid, ethosuximide, Drugs including, but not limited to, gabapentin, phenobarbital, solfeton and ferbatol; drugs used for the treatment of multiple sclerosis, such as tolterodine, oxybutynin, oxycodone, interferon beta-1b, interferon beta-1a, azathioprine, Including, but not limited to, methotrexate and glatiramer; agents used to treat Huntington's disease, such as amitriptyline, protriptyline, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline (Setraline), tetrabenazine, haloperidol, chlorpromazine, Including but not limited to thioridazine, sulpiride, quetiapine, clozapine, and risperidone; used in the treatment of diabetes Drugs such as PPAR ligands (eg, agonists and antagonists such as rosiglitazone, troglitazone and pioglitazone), insulin secretagogues (eg, glyburide, glimepiride, Chlopropamide, tolbutamide, and sulfonylureas such as glipizide) And non-sulfonyl secretagogues), α-glucosidase inhibitors (eg, acarbose, miglitol, and voglibose), insulin resistance improvers (eg, PPAR-γ agonists, eg, glitazones, biguanides, PTP-1B) Inhibitors, DPP-IV inhibitors, and 11 beta-HSD inhibitors), hepatic glucose release reducing compounds (eg, glucagon antagonists and metformin, eg, glucophage and glucophage XR), insulin and insulin derivatives (long-acting) B Anti-obesity agents such as β-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors, ciliary nerves, and the like. Nutritional factors and derivatives (eg, axocaine), appetite suppressants (eg, sibutramine), and lipase inhibitors (eg, orlistat) include, but are not limited to.

The administration mode of the compound of the present invention and the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Such dosage forms include, for example,
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different administration routes with a time difference (for example, in the order of the composition of the present invention → the concomitant drug) Administration, or administration in the reverse order). Hereinafter, these administration forms are collectively abbreviated as the combination agent of the present invention.

  When administering the concomitant drug of the present invention, the concomitant drug and the compound of the present invention may be administered at the same time, but after administering the concomitant drug, the compound of the present invention may be administered. A concomitant drug may be administered after administration of the compound of the invention. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, A method of administering the compound of the present invention preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is mentioned. However, when the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administering the compound of the present invention. The method of administering is mentioned.

  Any amount of the concomitant drug can be set as long as side effects are not a problem. The daily dose as a concomitant drug varies depending on the dose, administration subject, administration route, target disease, symptom, etc. For example, when administered orally to a schizophrenic patient (adult, body weight about 60 kg) The dosage is about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer several times to several times (eg, 3 times).

  When the compound of the present invention is used in combination with a concomitant drug, the dosage of each drug can be reduced within a safe range in consideration of the opposite effects of those drugs.

  The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention, or (and) the above concomitant drug is mixed with a pharmaceutically acceptable carrier according to a known method, and a pharmaceutical composition such as a tablet ( (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, and the like, which are orally or parenterally (Eg, topical, rectal, intravenous, etc.) can be safely administered.

  As the pharmaceutically acceptable carrier that can be used for the production of the concomitant drug of the present invention, the same carriers as those used for the pharmaceutical composition of the present invention described above can be used.

  The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.

  The above concomitant drugs may be used in combination of two or more drugs at an appropriate ratio.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug can be used per 1 part by weight of the compound of the present invention.

  For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight with respect to the whole preparation, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.

  The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually in the range of about 0.01 to 99.9% by weight with respect to the whole preparation, preferably about 0.1 to about It is in the range of 50% by weight, more preferably in the range of about 0.5 to about 20% by weight.

  The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually in the range of about 1 to 99.99% by weight, preferably about 10 to about 90% with respect to the whole preparation. It is in the range of wt%.

  The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.

  As described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, and a dosage exceeding the above range may be necessary.

When the compounds of the present invention are used as radiolabels and / or PET tracers, administration is preferably performed intravenously. ^{Since 11} C and ¹⁸ F have nuclides with short half-lives of usually 20 and 110 minutes, radiotracers labeled with positron-emitting nuclides are generally administered intravenously within 1 hour of their synthesis. Is. When a radiolabeled PDE10A inhibitor of the present invention is administered to a human subject, the amount required for imaging is usually determined by the prescribing physician, and the amount is generally determined by the nuclide used. Varies according to the amount of radiation from One skilled in the art can appreciate that in most cases, an effective amount is an amount of a compound sufficient to produce radiation in the range of about 1-5 mCi. The mass associated with a PET tracer is in the form of a natural isotope, for example, ¹² C for an ¹¹ C PET tracer and ¹⁹ F for an ¹⁸ F PET tracer. This mass contains about 0.1 μg to about 50 μg of radiolabeled PDE10A inhibitor to avoid significant inhibition of PDE10A.

The following descriptive procedure may be utilized when performing a PET imaging test on a patient in a clinical setting situation. The human subject is not administered a drug or is administered an unlabeled PDE10A inhibitor or other drug prior to the day of testing. They also fast for at least 12 hours with free access to water. To administer the radiotracer, a 20G2 inch venous catheter is inserted into the contralateral ulnar vein. The administration of the PET tracer is often timed to coincide with the time of maximum (T _max ) or minimum (T _min ) concentration of the PDE10A inhibitor (or other intervention compound) in the blood.

A human subject is placed in a PET camera and a tracer dose of [ ¹¹ C] Compound (I) (<20 mCi) is administered by intravenous injection via a catheter. To analyze and quantify the unmetabolized [ ¹¹ C] (compound (I)) fraction in plasma, either arterial blood samples or venous blood samples are taken at appropriate time intervals during the PET scan. Images are acquired for up to 120 minutes. In order to determine the plasma concentration of any unlabeled PDE10A inhibitor (or other intervention compound) administered before the PET tracer, 1 ml of radiotracer was injected within 10 minutes and at the end of imaging. Obtain a blood sample.

A tomographic image is obtained by image reconstruction. To measure the distribution of radioactive tracers, a region of interest (ROI) is reconstructed on the reconstructed image including (but not limited to) the striatum, cerebellum and other specific brain regions or central nervous system areas. Draw. Using radiotracer uptake over time in these areas, including data from untreated drugs or data obtained under PDE10A inhibitor or other drug treatment at various dosages tested, time A radioactivity curve (TAC) is created. Data are expressed as radioactivity / unit time / unit volume (μCi / cc / mCi injection dose). The TAC data is processed to obtain quantitative parameters using various methods well known in the art, such as binding capacity (BP), which is proportional to the density of unoccupied PDE10A. The inhibition of PDE10A is then calculated based on the change in BP in the presence of the PDE10A inhibitor compared to BP in the untreated drug state at various dosages. Inhibition curves are generated by plotting the above data against the dose (concentration) of PDE10A inhibitor. By fitting the dose rate / inhibition curve, an ID ₅₀ value is obtained using the following formula:
B = A ₀ −A ₀ ^* I / (ID ₅₀ + I) + NS
(Where B is the% of the radiotracer in the tissue for each dose of the clinical candidate—dose / g, A ₀ is the specific binding radiotracer in the tissue in the absence of the PDE10A inhibitor; I is the injected dose of antagonist, ID ₅₀ is the dose of compound that inhibits the binding of specific radiotracer to PDE10A by 50%, and NS is the amount of non-specifically bound radiotracer.)

  Furthermore, the present compounds are useful in methods for preventing, treating, controlling, ameliorating or reducing the risk of diseases, disorders and conditions described herein. The dose of active ingredient in the composition may vary, but it must be such that the amount of active ingredient is such that a suitable dosage form is obtained. The active ingredient may be administered in dosages that provide optimal pharmaceutical efficacy to patients (animals and humans) in need of such treatment. The dosage selected will depend on the intended therapeutic effect, the route of administration, and the duration of treatment. The dose will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, the particular dietary restrictions he is adhering to, current medications, and other factors recognized by those skilled in the art. In general, dosage levels of between 0.01 and 10 mg / kg are administered daily to patients such as humans and the elderly. The dosage range is generally about 0.5 mg to 1.0 g / patient / day, which may be administered once or multiple times. In one aspect, the dosage range is from about 0.5 mg to 500 mg / patient / day, in another aspect, from about 0.5 mg to 200 mg / patient / day; and in yet another aspect, from about 5 mg to 50 mg / patient / day. Day. The pharmaceutical composition of the present invention may be provided, for example, in a solid dosage form containing about 0.5 mg to 500 mg of active ingredient, or containing about 1 mg to 250 mg of active ingredient. The pharmaceutical composition may be provided in a solid dosage form containing about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg of the active ingredient. For oral administration, the composition can be prepared with 1.0-1000 mg of active ingredient, eg 1, 5, 10, 15, 20, 25, 50, to adjust the dosage to the condition of the patient to be treated. 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice a day.

The compounds of the following examples were active in inhibiting the human PDE10A enzyme described in the following biological assays, generally with an IC ₅₀ of less than about 1 μM. Many of the compounds within the scope of the present invention were active in inhibiting the human PDE10A enzyme in the above assay and generally had an IC ₅₀ of less than about 0.1 μM. Such a result indicates the intrinsic activity of the compound in use as an inhibitor of the PDE10A enzyme. One skilled in the art can generally understand that a substance is considered to effectively inhibit PDE10A activity if the IC ₅₀ of the substance is about 1 μM or less, preferably about 0.1 μM or less. The present invention also includes compounds within the general scope of the present invention that have activity as inhibitors of other phosphodiesterase enzymes.

The PDE10A IC ₅₀ is a measure of the ability of a test compound to inhibit the activity of the PDE10A enzyme. In order to determine the selectivity of the test compound with respect to PDE10A, the IC ₅₀ of the compound was measured for PDE 1-9 and 11. In the table below, the selectivity is defined as a value obtained by dividing the _{IC 50} of test compounds for the most potently inhibited PDE other than PDE10A in _{IC 50} for PDE10A. PDEs that are most strongly inhibited other than PDE10A are listed.

  The compounds of the present invention exhibit excellent BBB (brain-blood barrier) permeability. The compound of the present invention has a% ID value calculated as total radioactivity in the brain (MBq) × 100 / injected radioactivity (MBq), preferably 1-10%, more preferably 2-3. 5%. The compounds of the present invention exhibit high specific binding to the putamen, which is a high PDE10A region. In addition, it has been shown that washout from non-specific regions in the brain (eg, cerebellum and frontal lobe) is faster than washout from specific regions (eg, putamen), the PET radioligand of the present invention Making the compound more attractive. Since the compounds of the present invention show efficacy, they are useful as PET radioligands for PDE10A.

  The present invention will be described in detail with reference to the following Reference Examples, Examples, Formulation Examples, and Test Examples, which are merely examples and do not limit the present invention and do not depart from the scope of the present invention. It may be varied within a range.

  The raw material or intermediate of the present invention can be produced by a method known per se or the method disclosed in WO2010-090737.

“Room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for the yield,% by volume for the solvent used in the chromatography, and% by weight for the other. Proton NMR spectra that cannot be confirmed by broad such as OH and NH protons are not described in the data. Then, 1,3 Jikaruboni Le of Gobutsu can be observed as optionally enol, or a mixture of keto and enol forms. For silica gel chromatography, Merck's Kiesselgel 60 was used, and for basic silica gel chromatography, Fuji Silysia Chemical's Chromatorex NH was used.

Other abbreviations used in the text have the following meanings.
s: singlet
d: doublet
dd: doublet of doublets
dt: doublet of triplets
t: triplet
tt: triplet of triplets
td: triplet of doublets
q: quartet
septet: septet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
¹ H-NMR: Proton nuclear magnetic resonance
HPLC: High performance liquid chromatography
THF: tetrahydrofuran
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
NMP: N-methylpyrrolidone
HOBt: 1-hydroxybenzotriazole
WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
DMTMM: 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate
DBU: 1,8-diazabicyclo [5.4.0] -7-undecene
LC-MS: Liquid chromatography / mass spectrometry spectrum
ESI: Electrospray ionization method
CDI: 1,1'-carbonyldiimidazole
dba: Dibenzylideneacetone
DIBAL: Diisobutylaluminum hydride
DME: 1,2-dimethoxyethane
DPPA: Diphenylphosphoryl azide
HMPA: Hexamethylphosphoric triamide Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate)
TEA: Triethylamine
TFA: trifluoroacetic acid
TMSCl: Trimethylsilyl chloride
Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
Rt: Retention time
PBS: phosphate buffered saline

  All reagents and solvents were of commercial quality and were used without further purification. Column chromatography was performed using Merck silica gel 60 (230-400 mesh). Compounds and / or intermediates were purified by preparative high performance liquid chromatography (preparative HPLC) using a Gilson high throughput purification system.

  The column was a reverse phase YMC CombiPrep Pro C18, S-5 μm, 19 × 50 mm. Gradient elution was used (flow rate 20 mL / min). Typically, it was started with 5% acetonitrile / 95% water and made 100% acetonitrile over 7 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA).

  Mass spectrometry was performed according to the liquid chromatography / mass spectrometry (LCMS) method. This method consists of a Waters LC-MS system (LCMS instrument, Agilent HP1100 HPLC and Micromass ZMD mass spectrometer, chromatography column, CAPCELL PAK C18, UG120, S-3 μm, 1.5 x 35 mm, solvent system, A 5-95% gradient of acetonitrile / water containing 0.04% TFA was used for 3.60 minutes (flow rate 0.5 mL / min molecular weight range 200-800; cone voltage 20 V; column temperature 40 ° C.). Recorded as the mass of the parent ion.

Reference example 1
1- [2- (Difluoromethoxy) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- [2- (Difluoromethoxy) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazin-4 (1H) -one (0.50 g, 1.369 mmol) and phenylhydrazine ( A solution of 0.269 mL, 2.74 mmol) in AcOH (5 mL) was refluxed for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M hydrochloric acid, saturated aqueous NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with hexane / AcOEt (7 / 3-0 / 10)) to give the title compound (0.38 g, 68% yield) as an off-white amorphous solid: ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.88 (3H, s), 6.37 (1H, t, J = 72.3 Hz), 6.57 (1H, dd, J = 8.1, 1.7 Hz), 7.09-7.16 (1H, m), 7.22-7.25 (2H, m), 7.34-7.42 (6H, m), 7.76-7.78 (2H, m). LC-MS (ESI) m / z 411 [M + H] ⁺ . Anal. Calcd for C ₂₁ H ₁₆ F ₂ N ₄ O ₃ : C, 61.15; H, 4.07; N, 13.79. Found: C, 61.23; H, 4.11; N, 13.71.

Reference example 2
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (3.41 g, 9.29 mmol) and phenylhydrazine A solution of (1.83 mL, 18.6 mmol) in AcOH (25 mL) was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M hydrochloric acid, 1 M aqueous NaOH solution and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with AcOEt) and crystallized from hexane / AcOEt to give the title compound (2.70 g, 71% yield) as colorless crystals: mp 139-141 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.98 (3H, s), 7.05 (1H, dd, J = 1.9, 7.9 Hz), 7.19 (1H, s), 7.34-7.47 (7H, m), 7.56 ( 1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 7.92 (1H, s). LC-MS (ESI) m / z 413 [M + H] ⁺ . Anal. Calcd for C ₂₁ H ₁₅ F ₃ N ₄ O ₂ : C, 61.17; H, 3.67; N, 13.59. Found: C, 61.15; H, 3.65; N, 13.57.

Reference example 3
1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

Mixture of 3-acetyl-1- (2-fluoro-4-iodophenyl) -5-methoxypyridazin-4 (1H) -one (2.02 g, 5.2 mmol) and N, N-dimethylformamide dimethyl acetal (30 mL) Was refluxed for 6 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.
A solution of the residue and phenylhydrazine (1.54 mL, 15.6 mmol) in AcOH (20 mL) was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M hydrochloric acid, 1 M aqueous NaOH solution and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with AcOEt) and recrystallized from MeOH to give the title compound (1.14 g, 45% yield) as pale yellow crystals: mp 194-196 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.90 (3H, s), 6.04 (1H, t, J = 8.5 Hz), 7.30-7.47 (7H, m), 7.54 (1H, dd, J = 1.9, 10.6 Hz ), 7.76 (1H, d, J = 2.3 Hz), 7.78 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 489 [M + H] ⁺ . Anal. Calcd for C ₂₀ H ₁₄ FIN ₄ O ₂ : C, 49.20; H, 2.89; N, 11.47.Found: C, 48.94; H, 3.01; N, 11.54.

Reference example 4
1- [2-Fluoro-4- (trifluoromethyl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.50 mmol), FSO ₂ A mixture of CF ₂ CO ₂ Me (0.318 mL, 2.5 mmol), HMPA (0.435 mL, 2.5 mmol) and CuI (114 mg, 0.6 mmol) in DMF (2.5 mL) was stirred at 90 ° C. under Ar atmosphere for 24 hours. did. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with hexane / AcOEt (1/1)) and recrystallized from hexane / AcOEt to give the title compound (71.7 mg, 33% yield) as off-white crystals. : Mp 169-171 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.92 (3H, s), 6.42-6.47 (1H, m), 7.22-7.26 (1H, m), 7.37-7.49 ( 7H, m), 7.80 (1H, d, J = 1.9 Hz), 7.84 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 431 [M + H] ⁺ . Anal. Calcd for C ₂₁ H ₁₄ F ₄ N ₄ O ₂ : C, 58.61; H, 3.28; N, 13.02.Found: C, 58.50; H, 3.36; N, 12.93.

Reference Example 5
5-Ethoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol), iodoethane ( A suspension of 0.040 mL, 0.50 mmol) and K ₂ CO ₃ (104 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with hexane / AcOEt (1/1)) to give the title compound (94.1 mg, 88% yield) as an off-white amorphous solid: ¹ H NMR ( 300 MHz, CDCl ₃ ): δ ppm 1.52 (3H, t, J = 6.8 Hz), 4.21 (2H, q, J = 6.8 Hz), 7.03 (1H, dd, J = 1.9, 7.9 Hz), 7.18 (1H , s), 7.33-7.46 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 7.94 (1H, s). LC-MS (ESI) m / z 427 [M + H] ⁺ . Anal. Calcd for C ₂₂ H ₁₇ F ₃ N ₄ O ₂ : C, 61.97; H, 4.02; N, 13.14. Found: C, 61.82; H, 4.15; N, 13.17.

Reference Example 6
5- (1-Methylethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol), 2- A suspension of iodopropane (0.050 mL, 0.50 mmol) and K ₂ CO ₃ (104 mg, 0.75 mmol) in DMF (1 mL) was stirred at 60 ° C. for 20 hours. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with hexane / AcOEt (1/1)) and crystallized from hexane / AcOEt to give the title compound (79.5 mg, 72% yield) as colorless prism crystals. : Mp 137-139 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 1.38 (6H, d, J = 6.4 Hz), 4.96-5.09 (1H, m), 7.05 (1H, dd, J = 1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 8.01 (1H, s). LC-MS (ESI) m / z 441 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₉ F ₃ N ₄ O ₂ : C, 62.72; H, 4.35; N, 12.72. Found: C , 62.74; H, 4.40; N, 12.81.

Reference Example 7
5- (Cyclopropylmethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol), (bromomethyl ) A suspension of cyclopropane (0.048 mL, 0.50 mmol) and K ₂ CO ₃ (104 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with hexane / AcOEt (1/1)) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless prism crystals: mp 72-78 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J = 7.2 Hz), 7.04 (1H, dd, J = 2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m / z 453 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₁₉ F ₃ N ₄ O ₂ 0.5H ₂ O: C, 62.47; H, 4.37; N, 12.14.Found: C, 62.19; H, 4.41; N, 12.15.

Reference Example 8
5- (Difluoromethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (398 mg, 1.0 mmol), CF ₂ A mixture of ClCO ₂ Na (305 mg, 2.0 mmol), K ₂ CO ₃ (207 mg, 1.5 mmol), DMF (2 mL) and H ₂ O (0.4 mL) was stirred at 100 ° C. for 6 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with hexane / AcOEt (3/1)) and crystallized from hexane / AcOEt to give the title compound (267 mg, 59% yield) as colorless prism crystals. Mp 132-134 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 7.06 (1H, dd, J = 2.3, 8.3 Hz), 7.16-7.66 (10H, m), 7.82 (1H, d, J = 1.9 Hz), 8.33 (1H, s). LC-MS (ESI) m / z 449 [M + H] ⁺ . Anal. Calcd for C ₂₁ H ₁₃ F ₅ N ₄ O ₂ : C, 56.26; H , 2.92; N, 12.50. Found: C, 55.98; H, 2.82; N, 12.43.

Reference Example 9
5- (Difluoromethoxy) -1- (2-fluorophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluorophenyl) -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (557 mg, 1.6 mmol), CF ₂ ClCO ₂ Na ( A mixture of 488 mg, 3.2 mmol), K ₂ CO ₃ (332 mg, 2.4 mmol), DMF (3 mL) and H ₂ O (0.6 mL) was stirred at 100 ° C. overnight. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with hexane / AcOEt (2/1)) and crystallized from hexane / AcOEt to give the title compound (485 mg, 76% yield) as colorless prism crystals. Mp 109-114 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 6.46 (1H, dd, J = 1.5, 7.9 Hz), 7.00-7.06 (1H, m), 7.08-7.59 (9H, m), 7.80 (1H, d, J = 1.9 Hz), 8.20 (1H, s). LC-MS (ESI) m / z 399 [M + H] ⁺ .Anal. Calcd for C ₂₀ H ₁₃ F ₃ N ₄ O ₂ : C, 60.30; H, 3.29; N, 14.07. Found: C, 60.50; H, 3.41; N, 14.20.

Reference Example 10
5- (2-Methoxyethoxy) -3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one

5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [3- (trifluoromethyl) phenyl] pyridazin-4 (1H) -one (100 mg, 0.25 mmol), 2- A suspension of bromoethyl methyl ether (0.070 mL, 0.75 mmol) and K ₂ CO ₃ (104 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with hexane / AcOEt (1/2)) to give the title compound (89.9 mg, 79% yield) as a pale yellow amorphous solid: ¹ H NMR ( 300 MHz, CDCl ₃ ): δ ppm 3.45 (3H, s), 3.78-3.81 (2H, m), 4.42-4.44 (2H, m), 7.02 (1H, dd, J = 1.9, 7.9 Hz), 7.20 ( 1H, s), 7.34-7.45 (7H, m), 7.55 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J = 1.9 Hz), 8.29 (1H, s). LC-MS (ESI ) m / z 457 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₉ F ₃ N ₄ O ₃・ 0.25H ₂ O: C, 59.93; H, 4.26; N, 12.16. Found: C, 59.87; H, 4.09; N, 12.15.

Reference Example 11
1- [2-Fluoro-4- (trifluoromethoxy) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-acetyl-1- [2-fluoro-4- (trifluoromethoxy) phenyl] -5-methoxypyridazin-4 (1H) -one (2.8 g, 8.1 mmol) and N, N-dimethylformamide diisopropyl acetal (8.5 A solution of mL, 40 mmol) in toluene (50 mL) was refluxed for 5 hours. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure.
A solution of the residue and phenylhydrazine (2.0 mL, 20 mmol) in AcOH (30 mL) was refluxed for 3 hours. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The residue was diluted with AcOEt and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (10 / 90-100 / 0 AcOEt / hexane) to obtain 2.4 g of a crude product.
1 g of the crude product was purified by preparative HPLC, and the combined fractions were concentrated under reduced pressure. The residue solution was basified with saturated aqueous NaHCO ₃ and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residual crystals were recrystallized from AcOEt / hexane to give the title compound (0.66 g) as white crystals: mp 117-118 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.90 (3H, s ), 6.43 (1H, t, J = 8.7 Hz), 6.85-6.90 (1H, m), 7.09 (1H, dd, J = 11.5, 1.7 Hz), 7.34 (1H, d, J = 1.9 Hz), 7.35 -7.47 (5H, m), 7.77 (1H, d, J = 2.3 Hz), 7.78 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 447 [M + H] ⁺ . Anal Calcd.for C ₂₁ H ₁₄ F ₄ N ₄ O ₃ : C, 56.51; H, 3.16; N, 12.55. Found: C, 56.51; H, 3.14; N, 12.61.
Preparative HPLC was performed under the following conditions.
Column: Waters SunFire Column C18 (30 × 50 mm S-5μm)
Column temperature: 25 ° C
Mobile phase: (A) 0.1% TFA-containing distilled water, (B) 0.1% TFA-containing acetonitrile gradient: 0 min (A / B = 90/10) → 1 min (A / B = 90/10) → 4.75 min ( (A / B = 0/100) → 7.40 minutes (A / B = 0/100) → 7.41 minutes (A / B = 90/10) → 8.50 minutes (A / B = 90/10)
Flow rate: 70 mL / min
Detector: UV 220 nm
Concentration: 100 mg / mL
Injection volume: 10 mL

Reference Example 12
1- (3-Bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-acetyl-1- (3-bromo-2-fluorophenyl) -5-methoxypyridazin-4 (1H) -one (2.98 g, 8.74 mmol) in N, N-dimethylformamide dimethyl acetal (30 mL) The mixture was heated to reflux for 3.5 hours. The mixture was concentrated under reduced pressure. AcOH (30 mL) and phenylhydrazine (1.72 mL, 17.5 mmol) were added to the residue. The mixture was heated to reflux for 4 hours. The mixture was diluted with 1 M hydrochloric acid, extracted with AcOEt, washed with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and recrystallized with EtOH to give the title compound (2.29 g, 59% yield) as a yellow solid: mp 186-191 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.77 (3H, s), 6.99 (1H, d, J = 1.9 Hz), 7.08-7.15 (1H, m), 7.17-7.26 (1H, m), 7.28-7.47 (5H , m), 7.74-7.86 (2H, m), 8.55 (1H, d, J = 2.3 Hz). Anal. Calcd for C ₂₀ H ₁₄ BrFN ₄ O ₂ : C, 54.44; H, 3.20; N, 12.70. Found: C, 54.70; H, 3.30; N, 12.82.

Reference Example 13
1- [4- (Cyclopropylethynyl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol ), Cyclopropylethylene (0.0846 mL, 1.0 mmol), i-Pr ₂ NEt (0.348 mL, 2.0 mmol), CuI (9.5 mg, 0.05 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (17.5 mg, 0.025 mmol) And a mixture of PPh ₃ (6.6 mg, 0.025 mmol) in DMF (1 mL) was heated at 40 ° C. for 90 min under Ar. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexanes to give the title compound (181 mg, 85% yield) as a yellow solid: mp 145-146 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 0.74-0.82 (2H, m), 0.88-0.98 (2H, m), 1.58 (1H, tt, J = 8.2, 5.1 Hz), 3.77 (3H, s), 6.91-7.01 (2H, m), 7.20 (1H, dd, J = 8.3, 1.1 Hz), 7.28-7.51 (6H, m), 7.78 (1H, d, J = 1.9 Hz), 8.47 (1H, d, J = 1.9 Hz). Anal. Calcd for C ₂₅ H ₁₉ FN ₄ O ₂ : C, 70.41; H, 4.49; N, 13.14.Found: C, 70.33; H, 4.60; N, 13.08.

Reference Example 14
1- (4-Cyclopropyl-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (255 mg, 0.5 mmol ), Cyclopropylboronic acid (55.8 mg, 0.65 mmol), K ₃ PO ₄ (372 mg, 1.75 mmol), Pd (OAc) ₂ (5.6 mg, 0.025 mmol) and tricyclohexylphosphine (14 mg, 0.05 mmol) A mixture in toluene (2.25 mL) and water (0.11 mL) was heated at 100 ° C. for 4 h under Ar. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexane to give the title compound (128 mg, 64% yield) as a white solid: mp 140-142 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 0.70-0.82 (2H, m), 0.96-1.10 (2H, m), 1.94-2.09 (1H, m), 3.76 (3H, s), 6.87-7.01 (3H, m), 7.09-7.18 (1H , m), 7.28-7.50 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 8.44 (1H, d, J = 1.9 Hz). Anal. Calcd for C ₂₃ H ₁₉ FN ₄ O ₂ : C, 68.65; H, 4.76; N, 13.92. Found: C, 68.47; H, 4.82; N, 13.84.

Reference Example 15
1- [4- (3,6-Dihydro-2H-pyran-4-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (459 mg, 0.9 mmol ), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (210 mg, 1.0 mmol), Pd (PPh ₃ ) ₄ (52 mg, 0.045 mmol), Na ₂ CO ₃ (212 mg, 2.0 mmol) ), DME (4 mL) and H ₂ O (1 mL) were refluxed overnight under an Ar atmosphere. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from THF / MeOH to give the title compound (364 mg, 91% yield) as a white solid: mp 229-231 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 2.40-2.50 (2H, m), 3.77 (3H, s), 3.82 (2H, t, J = 5.5 Hz), 4.22-4.27 (2H, m), 6.43-6.48 (1H, m), 6.97 (1H, d, J = 1.9 Hz), 7.02 (1H, t, J = 8.7 Hz), 7.29-7.46 (6H, m), 7.52 (1H, dd, J = 1.9, 12.8 Hz), 7.79 (1H, d, J = 1.9 Hz), 8.48 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 445 [M + H] ⁺ . Anal. Calcd for C ₂₅ H ₂₁ FN ₄ O ₃ : C, 67.56; H, 4.76; N, 12.61.Found: C, 67.31; H, 4.58; N, 12.52.

Reference Example 16
1- [2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- [4- (3,6-Dihydro-2H-pyran-4-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( A mixture of 1H) -one (300 mg, 0.675 mmol), 10% Pd-C (50% wet, 300 mg), THF (30 mL) and MeOH (30 mL) was hydrogenated at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH / H ₂ O to give the title compound (255 mg, 85% yield) as a white solid: mp 187-189 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 1.57-1.83 (4H, m), 2.72-2.82 (1H, m), 3.45-3.58 (2H, m), 3.90 (3H, s), 4.09 (2H, td, J = 3.0, 11.3 Hz), 6.35 ( 1H, t, J = 8.3 Hz), 6.86 (1H, dd, J = 1.5, 8.3 Hz), 7.03 (1H, dd, J = 1.9, 12.8 Hz), 7.28 (1H, d, J = 1.9 Hz), 7.35-7.46 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 7.79 (1H, d, J = 2.6 Hz). LC-MS (ESI) m / z 447 [M + H] ⁺ . Anal. Calcd for C ₂₅ H ₂₃ FN ₄ O ₃ : C, 67.25; H, 5.19; N, 12.55. Found: C, 67.13 H, 5.13; N, 12.57.

Reference Example 17
1- [2-Fluoro-4- (3-fluoroazetidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3- 1 of fluoroazetidine hydrochloride (66.9 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) The mixture in, 4-dioxane (2.5 mL) was heated at 90 ° C. under N ₂ for 13 hours. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexane to give the title compound (88 mg, 40% yield) as a pale yellow solid: mp 162-163 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) : δ ppm 3.76 (3H, s), 3.86-4.04 (2H, m), 4.12-4.29 (2H, m), 5.36-5.64 (1H, m), 6.25 (1H, dd, J = 8.5, 2.1 Hz) , 6.48 (1H, dd, J = 12.8, 2.3 Hz), 6.81-6.95 (2H, m), 7.25-7.48 (5H, m), 7.77 (1H, d, J = 1.9 Hz), 8.36 (1H, d Anal. Calcd for C ₂₃ H ₁₉ F ₂ N ₅ O ₂ : C, 63.44: H, 4.40: N, 16.08. Found: C, 63.62: H, 4.44: N, 15.92.

Reference Example 18
1- [4- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3, 3-Difluoroazetidine hydrochloride (77.7 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) Of 1,4-dioxane (2.5 mL) was heated at 90 ° C. under Ar for 16 h. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexane to give the title compound (123 mg, 54% yield) as a pale yellow solid: mp 204-206 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz) : δ ppm 3.76 (3H, s), 4.35 (4H, t, J = 12.4 Hz), 6.36 (1H, dd, J = 8.9, 2.4 Hz), 6.61 (1H, dd, J = 12.8, 2.3 Hz), 6.87-6.99 (2H, m), 7.25-7.49 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 8.38 (1H, d, J = 1.5 Hz). Anal. Calcd for C ₂₃ H ₁₈ F ₃ N ₅ O ₂ : C, 60.93; H, 4.00; N, 15.45. Found: C, 61.00; H, 3.99; N, 15.50.

Reference Example 19
1- [4- (3,3-Difluoropyrrolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- on

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (204 mg, 0.4 mmol ), 3,3-difluoropyrrolidine hydrochloride (71.8 mg, 0.5 mmol), Pd ₂ (dba) ₃ (9.2 mg, 0.01 mmol), Xantphos (23.1 mg, 0.04 mmol) and NaOtBu (96.1 mg, 1.0 mmol) The suspension of 1,4-dioxane (2 mL) was stirred at 90 ° C. for 3 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography followed by purification by preparative HPLC. Recrystallization from MeOH / H ₂ O gave the title compound (21.0 mg, 11% yield) as a yellow solid: mp 195-197 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 2.46- 2.60 (2H, m), 3.52 (2H, t, J = 7.2 Hz), 3.66 (2H, t, J = 12.8 Hz), 3.89 (3H, s), 6.09 (1H, dd, J = 2.6, 9.0 Hz ), 6.23 (1H, dd, J = 2.6, 13.9 Hz), 6.33 (1H, t, J = 9.0 Hz), 7.25 (1H, d, J = 1.9 Hz), 7.33-7.44 (5H, m), 7.71 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 468 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₀ F ₃ N ₅ O ₂ : C, 61.67; H, 4.31; N, 14.98.Found: C, 61.51; H, 4.38; N, 14.89.
Preparative HPLC was performed under the following conditions.
Column: Waters SunFire Column C18 (30 × 50 mm S-5 μm)
Column temperature: 25 ° C
Mobile phase: (A) Distilled water containing 0.1% TFA, (B) Acetonitrile gradient containing 0.1% TFA: 0 minutes (A / B = 60/40) → 1 minute (A / B = 60/40) → 4.75 minutes ( (A / B = 0/100) → 7.40 minutes (A / B = 0/100) → 7.41 minutes (A / B = 60/40) → 8.50 minutes (A / B = 60/40)
Flow rate: 70 mL / min
Detector: UV 220 nm
Concentration: 50 mg / mL
Injection volume: 0.150 mL
Retention time: 2.44 minutes

Reference Example 20
1- [2-Fluoro-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (488 mg, 1.0 mmol), 3, 3,4,4-tetrafluoropyrrolidine hydrochloride (215 mg, 1.2 mmol), Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol) and NaOtBu (250 mg, 2.6 mmol) Of 1,4-dioxane (5 mL) was stirred at 90 ° C. for 6 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (eluted with hexane / AcOEt (1 / 1-0 / 1)) and crystallized from hexane / AcOEt to give the title compound (366 mg, 73% yield) as white Obtained as a solid: mp 175-177 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.75-3.89 (7H, m), 6.10 (1H, ddd, J = 0.8, 2.6, 9.0 Hz), 6.26 (1H, dd, J = 2.6, 13.6 Hz), 6.35 (1H, t, J = 9.0 Hz), 7.27 (1H, d, J = 1.9 Hz), 7.34-7.46 (5H, m), 7.71 (1H, d-J = 2.6 Hz), 7.78 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 504 [M + H] ⁺ .Anal. Calcd for C ₂₄ H ₁₈ F ₅ N ₅ O ₂ : C, 57.26; H, 3.60; N, 13.91. Found: C, 57.17; H, 3.61; N, 13.79.

Reference Example 21
1- [4- (3,3-Difluoropiperidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- on

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3, Of 3-difluoropiperidine hydrochloride (94.6 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) A mixture in 1,4-dioxane (2.5 mL) was heated at 90 ° C. under Ar for 14 h. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexane to give the title compound (132 mg, 55% yield) as a yellow solid: mp 182-187 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 1.68-1.81 (2H, m), 1.97-2.16 (2H, m), 3.34-3.43 (2H, m), 3.67 (2H, t, J = 11.9 Hz), 3.76 (3H, s), 6.73- 7.10 (4H, m), 7.24-7.50 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 1.9 Hz). Anal. Calcd for C ₂₅ H ₂₂ F ₃ N ₅ O ₂ : C, 62.36; H, 4.61; N, 14.55. Found: C, 62.60; H, 4.60; N, 14.31.

Reference Example 22
1- [4- (4,4-Difluoropiperidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- on

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (408 mg, 0.8 mmol ), 4,4-difluoropiperidine hydrochloride (158 mg, 1.0 mmol), Pd ₂ (dba) ₃ (36.6 mg, 0.04 mmol), Xantphos (92.6 mg, 0.16 mmol) and NaOtBu (192 mg, 2.0 mmol) The suspension of 1,4-dioxane (4 mL) was stirred at 90 ° C. for 3 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with hexane / AcOEt (1 / 2-0 / 1)) and crystallized from hexane / AcOEt to give the title compound (96.0 mg, 25% yield) in yellow Obtained as a green solid: mp 192-194 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 2.01-2.14 (4H, m), 3.38-3.42 (4H, m), 3.89 (3H, s), 6.31 (1H, t, J = 9.0 Hz), 6.47 (1H, dd, J = 2.3, 9.0 Hz), 6.61 (1H, dd, J = 2.6, 14.3 Hz), 7.25 (1H, d, J = 1.9 Hz) ), 7.34-7.45 (5H, m), 7.73 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 482 [M + H] ⁺ . Anal. Calcd for C ₂₅ H ₂₂ F ₃ N ₅ O ₂ : C, 62.36; H, 4.61; N, 14.55. Found: C, 62.13; H, 4.62; N, 14.43.

Reference Example 23
1- [2-Fluoro-4- (2-oxo-1,3-oxazolidine-3-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 2- 1,4-Oxazolidone (52.2 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol) and K ₃ PO ₄ (212 mg, 1.0 mmol) The suspension of dioxane (2 mL) was refluxed for 1.5 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH / H ₂ O to give the title compound (159 mg, 71% yield) as a pale yellow solid: mp 218-220 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.90 (3H, s), 4.03-4.08 (2H, m), 4.51-4.56 (2H, m), 6.42 (1H, t, J = 9.0 Hz), 7.01 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.30 (1H, d, J = 1.9 Hz), 7.35-7.45 (5H, m), 7.66 (1H, dd, J = 2.3, 13.6 Hz), 7.78 (2H, d, J-1.9 Hz). LC-MS (ESI) m / z 448 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₈ FN ₅ O ₄ : C, 61.74; H, 4.06; N, 15.65. Found: C, 61.48; H, 4.07; N, 15.54.

Reference Example 24
4- {3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl} morpholin-3-one

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3- Morpholinone (60.7 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol) and K ₃ PO ₄ (212 mg, 1.0 mmol) 1,4- The suspension of dioxane (2 mL) was refluxed for 6 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with AcOEt) and recrystallized from MeOH / H ₂ O to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.75-3.79 (2H, m), 3.90 (3H, s), 4.04-4.07 (2H, m), 4.35 (2H, s), 6.41 (1H , t, J = 9.0 Hz), 7.00 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.33-7.46 (6H, m), 7.78-7.80 ( LC-MS (ESI) m / z 462 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₀ FN ₅ O ₄ : C, 62.47; H, 4.37; N, 15.18. Found: C , 62.31; H, 4.33; N, 15.25.

Reference Example 25
1- [2-Fluoro-4- (1H-imidazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), imidazole ( 40.8 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol) and Cs ₂ CO ₃ (326 mg, 1.0 mmol) of 1,4-dioxane ( The suspension was refluxed for 4 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with AcOEt / THF (1 / 0-0 / 1)) and crystallized from MeOH to give the title compound (16.5 mg, 8% yield) as a white solid Obtained: mp 235-236 ° C (dec); ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.93 (3H, s), 6.49 (1H, t, J = 8.7 Hz), 7.03 (1H, ddd, J = 1.1, 2.3, 8.7 Hz), 7.22-7.27 (3H, m), 7.35 (1H, d, J = 1.9 Hz), 7.38-7.49 (5H, m), 7.80 (1H, d, J = 1.9 Hz) ), 7.82 (1H, d, J = 2.6 Hz), 7.86 (1H, t, J = 1.1 Hz). LC-MS (ESI) m / z 429 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₇ FN ₆ O ₂ : C, 64.48; H, 4.00; N, 19.62.Found: C, 64.35 H, 3.90; N, 19.43.

Reference Example 26
1- [2-Fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

3-acetyl-1- [2-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (243 mg, 0.708 mmol) of N, A mixture in N-dimethylformamide dimethyl acetal (2.4 mL) was heated to reflux for 2 hours. The mixture was concentrated under reduced pressure. AcOH (2.4 mL) and phenylhydrazine (0.139 mL, 1.42 mmol) were added to the residue. The mixture was heated to reflux for 2 hours. The mixture was diluted with 1 M hydrochloric acid, extracted with AcOEt, washed with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, basic silica gel column chromatography (hexane / AcOEt = 20/80 to 0/100) and recrystallized with EtOH / AcOEt / hexane to give the title compound (193 mg, 62% yield) as a pale yellow solid: mp 218-221 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.78 (3H, s), 3.91 (3H, s), 6.97 (2H, d, J = 1.9 Hz), 7.13-7.50 (6H, m), 7.72- 7.84 (2H, m), 7.93 (1H, s), 8.18 (1H, d, J = 2.3 Hz), 8.55 (1H, d, J = 1.9 Hz).

Reference Example 27
1- [2-Fluoro-4- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol ), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (104 mg, 0.50 mmol), Pd (PPh ₃ ) ₄ (29 mg, 0.025 mmol), Na ₂ CO ₃ (106 mg, 1.0 mmol), A mixture of DME (4 mL) and H ₂ O (1 mL) was refluxed overnight under an Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with THF) and recrystallized from MeOH / H ₂ O to give the title compound (162 mg, 81% yield) as a white solid: mp 195-197 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.91 (3H, s), 3.96 (3H, s), 6.38 (1H, t, J = 8.3 Hz), 7.06 (1H, ddd, J = 0.8 , 1.9, 8.3 Hz), 7.23 (1H, dd, J = 1.9, 12.8 Hz), 7.30 (1H, d, J = 1.9 Hz), 7.36-7.47 (5H, m), 7.64 (1H, s), 7.74 (1H, d, J = 0.8 Hz), 7.79 (1H, d, J = 1.9 Hz), 7.81 (1H, d, J = 2.6 Hz). LC-MS (ESI) m / z 443 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₁₉ FN ₆ O ₂ : C, 65.15; H, 4.33; N, 18.99. Found: C, 65.15; H, 4.30; N, 19.02.

Reference Example 28
1- [2-Fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

3-acetyl-1- [2-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (200 mg, 0.585 mmol) of N, A mixture in N-dimethylformamide dimethyl acetal (2.0 mL) was heated to reflux for 3 hours. The mixture was concentrated under reduced pressure. AcOH (2.0 mL) and phenylhydrazine (0.115 mL, 1.17 mmol) were added to the residue. The mixture was heated to reflux for 3 hours. The mixture was diluted with 1 M hydrochloric acid, extracted with AcOEt, washed with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and HPLC and recrystallized with EtOH / hexane to give the title compound (118 mg, 46% yield) as a white solid: mp 93-102 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.78 (3H, s), 3.89 (3H, s), 6.91 (1H, d, J = 1.9 Hz), 7.20-7.52 (7H, m), 7.63-7.71 (1H, m), 7.78 (1H, d, J = 1.9 Hz), 7.83 (1H, s), 8.10 (1H, s), 8.53 (1H, d, J = 1.6 Hz). Anal. Calcd for C ₂₄ H ₁₉ FN ₆ O ₂・ 1.3H ₂ O: C, 61.88; H, 4.67; N, 18.04.Found: C, 61.63; H, 4.64; N, 18.09.
Preparative HPLC was performed under the following conditions.
Column: YMC CombiPrep Pro C18 RS (50 × 20 mm I.D.S-5μm, 8 nm)
Column temperature: 25 ° C
Mobile phase: (A) Distilled water containing 0.1% TFA, (B) Acetonitrile gradient containing 0.1% TFA: 0 min (A / B = 95/5) → 1.00 min (A / B = 95/5) → 5.70 min ( (A / B = 0/100) → 7.30 minutes (A / B = 0/100) → 7.40 minutes (A / B = 95/5) → 8.00 minutes (A / B = 95/5)
Flow rate: 20 mL / min
Detector: UV 220 nm
Concentration: 89 mg / mL
Injection volume: 100 μL

Reference Example 29
1- {4- [1- (Difluoromethyl) -1H-pyrazol-4-yl] -2-fluorophenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -ON

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (230 mg, 0.45 mmol ), 1- (difluoromethyl) -1H-pyrazole-4-boronic acid pinacol ester (122 mg, 0.50 mmol), Pd (PPh ₃ ) ₄ (17 mg, 0.015 mmol), Na ₂ CO ₃ (106 mg, 1.0 mmol), DME (4 mL) and H ₂ O (1 mL) were refluxed under Ar atmosphere for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with AcOEt) and recrystallized from MeOH / H ₂ O to give the title compound (183 mg, 85% yield) as a white solid: mp 185-187 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.92 (3H, s), 6.41 (1H, t, J = 8.3 Hz), 7.03-7.48 (10H, m), 7.79 (1H, d, J = 1.9 Hz), 7.83 (1H, d, J = 2.3 Hz), 7.91 (1H, d, J = 0.8 Hz). LC-MS (ESI) m / z 479 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₁₇ F ₃ N ₆ O ₂ : C, 60.25; H, 3.58; N, 17.57.Found: C, 60.19; H, 3.48; N, 17.52.

Reference Example 30
1- [2-Fluoro-4- (1,3-oxazol-2-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 2- A mixture of (tributylstannanyl) -1,3-oxazole (0.209 mL, 1.0 mmol) and Pd (PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) in 1,4-dioxane (3 mL) under Ar Heated to reflux for hours. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100, And AcOEt / MeOH = 100/0 to 70/30) and recrystallized with EtOH / hexane to give the title compound (113 mg, 53% yield) as a yellow solid: mp 223-225 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.79 (3H, s), 7.02 (1H, d, J = 1.9 Hz), 7.16 (1H, t, J = 8.3 Hz), 7.31-7.51 ( 6H, m), 7.77-7.83 (2H, m), 7.96 (1H, dd, J = 11.5, 1.7 Hz), 8.34 (1H, s), 8.55 (1H, d, J = 2.6 Hz). Anal. Calcd for C ₂₃ H ₁₆ FN ₅ O ₃・ 0.1H ₂ O: C, 64.06; H, 3.79; N, 16.24.Found: C, 63.92; H, 3.67; N, 16.23.

Reference Example 31
1- (2-Fluoro-4-pyridin-2-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-Fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl trifluoromethanesulfonate (200 mg, 0.392 mmol ), (2-pyridine) cyclic triol borate lithium salt (167 mg, 0.784 mmol), 2- (di-tert-butylphosphino) biphenyl (12.9 mg, 0.0431 mmol), CuI (14.9 mg, 0.0784 mmol) and Pd A mixture of (OAc) ₂ (4.4 mg, 0.0196 mmol) in DMF (1.2 mL) was heated at 80 ° C. for 13 h under Ar. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and recrystallized with AcOEt / hexane to give the title compound (68.9 mg, 40% yield) as a pale yellow solid : mp 206-208 ° C; ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.80 (3H, s), 7.01 (1H, d, J = 1.9 Hz), 7.11 (1H, t, J = 8.3 Hz), 7.31-7.53 (6H, m), 7.80 (1H, d, J = 1.9 Hz), 7.91-8.02 (2H, m), 8.08-8.20 (2H, m), 8.55 (1H, d, J = 1.9 Hz), 8.72 (1H, d, J = 4.5 Hz). Anal.Calcd for C ₂₅ H ₁₈ FN ₅ O ₂ : C, 68.33; H, 4.13; N, 15.94. Found: C, 68.15; H, 4.18 ; N, 15.83.

Reference Example 32
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

KOtBu (236 mg, 2.1 mmol) was added to 1- [2-fluoro-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl- To a solution of 1H-pyrazol-5-yl) pyridazin-4 (1H) -one (352 mg, 0.7 mmol) in DMSO (3.5 mL) was added in portions at room temperature. After stirring for 30 minutes, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (elution with hexane / AcOEt (1 / 1-0 / 1)), followed by purification by preparative HPLC. Recrystallization from MeOH / H ₂ O gave the title compound (105 mg, 32% yield) as a white solid: mp 212-214 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.91 ( 3H, s), 6.42 (1H, t, J = 9.0 Hz), 6.68-6.78 (2H, m), 6.87 (1H, ddd, J = 1.1, 2.6, 9.0 Hz), 7.07 (1H, dd, J = 2.6, 12.4 Hz), 7.33 (1H, d, J = 2.3 Hz), 7.36-7.48 (5H, m), 7.78-7.79 (2H, m). LC-MS (ESI) m / z 464 [M + H ] ⁺ .Anal. Calcd for C ₂₄ H ₁₆ F ₃ N ₅ O ₂ : C, 62.20; H, 3.48; N, 15.11. Found: C, 62.20; H, 3.51; N, 15.01.
Preparative HPLC was performed under the following conditions.
Column: YMC CombiPrep ODS-A (20 × 50 mm S-5 μm)
Column temperature: 25 ° C
Mobile phase: (A) Distilled water containing 0.1% TFA, (B) Acetonitrile gradient containing 0.1% TFA: 0.00 minutes (A / B = 60/40) → 1.00 minutes (A / B = 60/40) → 4.75 minutes ( (A / B = 0/100) → 7.39 minutes (A / B = 0/100) → 7.40 minutes (A / B = 100/0) → 7.50 minutes (A / B = 100/0)
Flow rate: 25 mL / min
Detector: UV 220 nm
Concentration: 33.3 mg / mL
Injection volume: 0.300 mL
Retention time: 2.35 minutes

Reference Example 33
1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (4.88 g, 10 mmol), pyrazole ( 0.681 g, 10 mmol), Cu ₂ O (0.143 g, 1 mmol), salicylaldoxime (0.549 g, 4 mmol) and Cs ₂ CO ₃ (6.52 g, 20 mmol) in CH ₃ CN (100 mL) The solution was refluxed for 5 hours under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with hexane / THF (1/2)) and recrystallized from EtOH / H ₂ O to give the title compound (1.90 g, 44% yield) as a pale yellow powder. Obtained as: mp 214-216 ° C; ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 3.92 (3H, s), 6.44 (1H, t, J = 9.0 Hz), 6.53 (1H, dd, J = 1.9 , 2.3 Hz), 7.30 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.34 (1H, d, J = 1.9 Hz), 7.37-7.48 (5H, m), 7.61 (1H, dd, J = 2.3, 12.4 Hz), 7.76 (1H, d, J = 1.9 Hz), 7.79 (1H, d, J = 1.9 Hz), 7.82 (1H, d, J = 2.3 Hz), 7.92 (1H, d, J = LC-MS (ESI) m / z 429 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₇ FN ₆ O ₂ : C, 64.48; H, 4.00; N, 19.62. Found: C, 64.41; H, 4.00; N, 19.54.

Reference Example 34
Ethyl 1- {3-fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl} -5-hydroxy- 1H-pyrazole-4-carboxylate

tert-butyl 1- {3-fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl} hydrazinecarboxylate A mixture of (2.02 g, 4.1 mmol), TFA (5 mL) and CH ₂ Cl ₂ (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure.
A suspension of the residue, diethyl ethoxymethylene malonate (0.829 mL, 4.1 mmol) and K ₂ CO ₃ (1.70 g, 12.3 mmol) in EtOH (20 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from EtOH to give the title compound (1.43 g, 67% yield) as a pale solid: mp 188-193 ° C; ¹ H NMR (300 MHz, CDCl ₃ ) : δ ppm 1.41 (3H, t, J = 7.2 Hz), 3.92 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 6.45 (1H, t, J = 9.0 Hz), 7.35 (1H, d, J = 1.9 Hz), 7.37-7.48 (5H, m), 7.55 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.77-7.82 (3H, m), 7.83 (1H, d, J = Anal.Calcd for C ₂₆ H ₂₁ FN ₆ O ₅ : C, 60.46; H, 4.10; N, 16.27.Found: C, 60.28; H, 4.17; N, 16.37.

Reference Example 35
1- [2-Fluoro-4- (5-hydroxy-1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

Ethyl 1- {3-fluoro-4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] phenyl} -5-hydroxy- A mixture of 1H-pyrazole-4-carboxylate (1.41 g, 2.73 mmol), 4 M NaOH (40 mL) and EtOH (40 mL) was refluxed for 4 hours. After cooling to room temperature, concentrated HCl (20 mL) was gradually added. The mixture was stirred at room temperature for 30 minutes and then refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with AcOEt / THF (2/1)) and recrystallized from THF / MeOH to give the title compound (387 mg, 32% yield) as a pale yellow solid: mp 221-229 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 3.78 (3H, s), 5.57 (1H, d, J = 1.5 Hz), 6.99 (1H, d, J = 1.9 Hz ), 7.14 (1H, t, J = 9.0 Hz), 7.31-7.51 (6H, m), 7.64-7.68 (1H, m), 7.79-7.84 (2H, m), 8.52 (1H, d, J = 1.9 Hz), 12.17 (1H, brs). LC-MS (ESI) m / z 445 [M + H] ⁺ .

Reference Example 36
1- {4- [5- (Difluoromethoxy) -1H-pyrazol-1-yl] -2-fluorophenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -ON

Reference Example 37
1- {4- [2- (Difluoromethyl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -2-fluorophenyl} -5-methoxy-3- (1-phenyl-1H -Pyrazol-5-yl) pyridazine-4 (1H) -one

1- [2-Fluoro-4- (5-hydroxy-1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -ON (373 mg, 0.84 mmol), CF ₂ ClCO ₂ Na (256 mg, 1.68 mmol), K ₂ CO ₃ (232 mg, 1.68 mmol), DMF (2.5 mL) and H ₂ O (0.5 mL) Was stirred at 100 ° C. for 2 hours. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with AcOEt) and recrystallized from AcOEt to give 1- {4- [5- (difluoromethoxy) -1H-pyrazol-1-yl] -2-fluorophenyl. } -5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (168 mg, 40% yield) was obtained as a pale yellow solid: mp 177-179 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.92 (3H, s), 6.07-6.08 (1H, m), 6.45 (1H, t, J = 9.0 Hz), 6.59 (1H, t, J = 71.8 Hz), 7.34-7.47 (7H, m), 7.58 (1H, dd, J = 2.3, 12.4 Hz), 7.61 (1H, d, J = 1.9 Hz), 7.79 (1H, d, J = 1.9 Hz ), 7.83 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 495 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₁₇ F ₃ N ₆ O ₃ : C, 58.30; H, 3.47; N, 17.00. Found: C, 58.17; H, 3.46; N, 16.91.
After further elution, 1- {4- [2- (difluoromethyl) -5-oxo-2,5-dihydro-1H-pyrazol-1-yl] -2 was obtained by recrystallization from MeOH / H ₂ O. -Fluorophenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (63.5 mg, 15% yield) was obtained as a white solid: mp 161 -163 ° C; ¹ H NMR (CDCl ₃ ) δ 3.91 (3H, s), 5.99 (1H, d, J = 4.1 Hz), 6.40 (1H, t, J = 60.7 Hz), 6.47 (1H, t, J = 8.7 Hz), 7.09 (1H, ddd, J = 1.1, 2.3, 8.7 Hz), 7.32 (1H, d, J = 1.9 Hz), 7.36-7.47 (6H, m), 7.79-7.81 (3H, m) LC-MS (ESI) m / z 495 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₁₇ F ₃ N ₆ O ₃・ 0.5H ₂ O: C, 57.26; H, 3.60; N, 16.69. Found: 57.38; H, 3.52; N, 16.78.

Reference Example 38
1- (2-Fluoro-5-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-acetyl-1- (2-fluoro-5-iodophenyl) -5-methoxypyridazin-4 (1H) -one (3.88 g, 10.0 mmol) in N, N-dimethylformamide dimethyl acetal (38.8 mL) The mixture was heated to reflux for 3 hours. The mixture was concentrated under reduced pressure. AcOH (38.8 mL) and phenylhydrazine (1.97 mL, 20.0 mmol) were added to the residue. The mixture was heated to reflux for 5 hours. The mixture was concentrated under reduced pressure, diluted with 1 M hydrochloric acid, extracted with AcOEt, washed with saturated aqueous NaHCO ₃ solution, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography. Purified by chromatography (hexane / AcOEt = 50/50 to 0/100) and triturated with AcOEt / hexane to give the title compound (2.95 g, 60% yield) as a yellow solid: ¹ H NMR (DMSO-d ₍₆ , 300 MHz): δ ppm 3.77 (3H, s), 6.99 (1H, d, J = 1.5 Hz), 7.23-7.50 (7H, m), 7.79 (1H, d, J = 1.9 Hz), 7.84 ( 1H, ddd, J = 8.7, 4.5, 2.3 Hz), 8.49 (1H, d, J = 2.6 Hz).

Reference Example 39
3- [1- (2-Fluorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine-4 (1H )-on

3-acetyl-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (197 mg, 0.600 mmol) in N, N-dimethylformamide The suspension of dimethylacetal (2.0 mL) was stirred at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. AcOH (2.0 mL) and 2-fluorophenylhydrazine (151 mg, 1.20 mmol) were added to the residue. The mixture was stirred at 100 ° C. for 1 hour. After evaporation of the solvent, the residue was diluted with saturated aqueous NaHCO ₃ solution (25 mL) and extracted with AcOEt (25 mL × 3). The combined organic layers were washed with brine (40 mL), dried over MgSO ₄ and evaporated. The residue was crystallized from AcOEt to give a crude solid which was recrystallized from EtOH / hexane to give the title compound (125 mg, 47% yield) as a white solid: mp 202-206 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 3.79 (3H, s), 6.64 (1H, d, J = 1.9 Hz), 6.96 (1H, t, J = 8.5 Hz), 7.23-7.33 ( 3H, m), 7.41-7.53 (2H, m), 7.71 (1H, d, J = 9.1 Hz), 7.84 (2H, dd, J = 4.0, 1.7 Hz), 7.94 (1H, dd, J = 12.3, 2.5 Hz), 8.48 (1H, d, J = 1.9 Hz), 8.65 (1H, d, J = 2.6 Hz). LC-MS (ESI) m / z 447 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₆ F ₂ N ₆ O ₂・ 0.4H ₂ O: C, 60.90; H, 3.73; N, 18.53.Found: C, 60.68; H, 3.69; N, 18.39.

Reference Example 40
3- [1- (3-Chlorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine-4 (1H) -on

3-acetyl-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (393 mg, 1.20 mmol) in N, N-dimethylformamide The suspension of dimethylacetal (4.0 mL) was stirred at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. AcOH (4 mL) and 3-chlorophenylhydrazine hydrochloride (429 mg, 2.40 mmol) were added to the residue. The mixture was stirred at 100 ° C. for 1 hour. After evaporation of the solvent, the residue was diluted with saturated aqueous NaHCO ₃ solution (25 mL) and extracted with AcOEt (25 mL × 3). The combined organic layers were washed with brine (40 mL), dried over MgSO ₄ and evaporated. The residue was crystallized from AcOEt to give a crude solid which was recrystallized from EtOH / hexane to give the title compound (242 mg, 44% yield) as a pale solid: mp 186-190 ° C ; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 3.80 (3H, s), 6.64 (1H, d, J = 1.9 Hz), 7.05 (1H, d, J = 1.9 Hz), 7.27-7.34 (1H, m), 7.44 (3H, dd, J = 16.6, 10.2 Hz), 7.34-7.52 (1H, m), 7.84 (3H, dd, J = 3.6, 1.7 Hz), 8.00 (1H, dd, J = 12.3, 2.1 Hz), 8.56 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 2.6 Hz): LC-MS (ESI) m / z 463 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₆ ClFN ₆ O ₂・ 0.03H ₂ O: C, 59.61; H, 3.49; N, 18.14.Found: C, 59.32; H, 3.50; N, 17.92.

Reference Example 41
1- [4- (3-tert-Butyl-2-oxoimidazolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (488 mg, 1.0 mmol), 1- tert-Butylimidazolidin-2-one (171 mg, 1.2 mmol), CuI (19 mg, 0.1 mmol), trans-1,2-diaminocyclohexane (0.024 mL, 0.2 mmol) and K ₃ PO ₄ (425 mg, A suspension of 2.0 mmol) in toluene (5 mL) was stirred at 80 ° C. for 24 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (eluted with hexane / AcOEt (1/1), AcOEt only, then AcOEt / MeOH (10/1)), recrystallized from AcOEt, Compound (198 mg, 39% yield) was obtained as a white solid: mp 238-239 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δppm 1.36 (9H, s), 3.29 (3H, s) , 3.44-3.59 (2H, m), 3.64-3.76 (2H, m), 6.92-7.03 (2H, m), 7.23-7.51 (6H, m), 7.70 (1H, dd, J = 14.1, 2.4 Hz) , 7.78 (1H, d, J = 1.9 Hz), 8.43 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 503 [M + H] ⁺ . Anal. Calcd for C ₂₇ H ₂₇ FN ₆ O ₃ : C, 64.53; H, 5.42; N, 16.72. Found: C, 64.31; H, 5.38; N, 16.58.

Reference Example 42
1- [2-Fluoro-4- (2-oxoimidazolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- [4- (3-tert-Butyl-2-oxoimidazolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- A mixture of 4 (1H) -one (503 mg, 1.0 mmol) in trifluoroacetic acid (3.0 mL) was stirred at 80 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was evaporated. The residue was recrystallized from AcOEt / MeOH to give the title compound (334 mg, 75% yield) as a pale yellow solid: mp 259-260 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δppm 3.40-3.50 (2H, m), 3.77 (3H, s), 3.82-3.93 (2H, m), 6.95 (1H, d, J = 2.3 Hz), 7.01 (1H, t, J = 9.0 Hz), 7.23 -7.49 (7H, m), 7.73 (1H, dd, J = 14.1, 2.4 Hz), 7.78 (1H, d, J = 1.9 Hz), 8.44 (1H, d, J = 1.9 Hz). LC-MS ( ESI) m / z 447 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₉ FN ₆ O ₃・ 0.75H ₂ O: C, 60.06; H, 4.49; N, 18.27. Found: C, 60.05; H , 4.26; N, 18.16.

Reference Example 43
1- {4- [3- (Difluoromethyl) -2-oxoimidazolidin-1-yl] -2-fluorophenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -ON

1- [2-Fluoro-4- (2-oxoimidazolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one A mixture of (100 mg, 0.22 mmol), sodium chlorodifluoroacetate (40 mg, 0.26 mmol) and 18-crown-6 (12 mg, 0.044 mmol) in acetonitrile (10 mL) was stirred at 90 ° C. for 20 hours. After cooling to room temperature, silica gel was added to the reaction mixture. The mixture was evaporated and purified by silica gel column chromatography (eluting with AcOEt / MeOH (1/0 to 10/1)) to give the title compound (2.5 mg, 2.3% yield) as a pale yellow powder. : ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 1.11-1.40 (4H, m), 3.61-3.86 (4H, m), 6.96 (1H, d, J = 1.9 Hz), 7.01-7.15 ( 1H, m), 7.16-7.50 (6H, m), 7.71 (1H, dd, J = 13.6, 2.3 Hz), 7.79 (1H, d, J = 2.3 Hz), 8.47 (1H, d, J = 1.9 Hz LC-MS (ESI) m / z 497 [M + H] ⁺ .

Reference Example 44
1- [3- (3,6-Dihydro-2H-pyran-4-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (441 mg, 1.0 mmol), 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyran (231 mg, 1.1 mmol), Pd (PPh ₃ ) ₄ (57.8 mg, 0.05 mmol) and Na ₂ CO ₃ (233 mg, 2.2 mmol) in DME (8.8 mL) and water (2.2 mL) were heated to reflux under N ₂ for 15 h. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with EtOH / hexane to give the title compound (380 mg, 85% yield) as a white solid: mp 138-141 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 2.42 (2H, brs), 3.74-3.89 (5H, m), 4.21-4.29 (2H, m), 6.15 (1H, brs), 6.92-7.10 (2H, m), 7.17-7.59 (7H, m ), 7.78 (1H, d, J = 1.9 Hz), 8.52 (1H, s). Anal.Calcd for C ₂₅ H ₂₁ FN ₄ O ₃ : C, 67.56; H, 4.76; N, 12.61. Found: C, 67.42; H, 4.83; N, 12.44.

Reference Example 45
1- [2-Fluoro-3- (tetrahydro-2H-pyran-4-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- [3- (3,6-Dihydro-2H-pyran-4-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( A mixture of 1H) -one (190 mg, 0.427 mmol) and Pd / C (10% Pd, 50% water content, 19 mg) in MeOH (10 mL) was stirred under H ₂ at room temperature for 16 hours. The mixture was filtered through a pad of celite, concentrated under reduced pressure, purified by basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100), recrystallized from EtOH / hexane, and the title compound ( 152 mg, 79% yield) was obtained as a pale yellow solid: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 1.60-1.85 (4H, m), 3.39-3.56 (3H, m), 3.77 (3H, s), 3.91-4.04 (2H, m), 6.92-7.04 (2H, m), 7.21 (1H, t, J = 8.1 Hz), 7.27-7.54 (6H, m), 7.78 (1H, d , J = 1.9 Hz), 8.49 (1H, d, J = 1.9 Hz).

Reference Example 46
1- (2-Fluoro-3-morpholin-4-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (3-Bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (221 mg, 0.5 mmol), morpholine ( 0.0525 mL, 0.6 mmol), NaOt-Bu (67.3 mg, 0.7 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) The mixture in was heated at 90 ° C. under Ar for 18 hours. The mixture was diluted with aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) And recrystallized with AcOEt / hexane and EtOH / hexane to give the title compound (139 mg, 59% yield) as a pale yellow solid: mp 187-189 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 2.97-3.08 (4H, m), 3.70-3.80 (7H, m), 6.61-6.72 (1H, m), 6.96 (1H, d, J = 1.5 Hz), 7.06-7.17 ( 2H, m), 7.26-7.47 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 8.50 (1H, d, J = 1.9 Hz). Anal. Calcd for C ₂₄ H ₂₂ FN ₅ O ₃ : C, 64.42; H, 4.96; N, 15.65. Found: C, 64.47; H, 4.99; N, 15.55.

Reference Example 47
1- [3- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (177 mg, 0.4 mmol), 3, 3-Difluoroazetidine hydrochloride (62.2 mg, 0.48 mmol), NaO-t-Bu (99.9 mg, 1.04 mmol), Xantphos (99.9 mg, 0.173 mmol) and Pd ₂ (dba) ₃ (39.7 mg, 0.043 mmol) Of 1,4-dioxane (2 mL) was heated at 90 ° C. under N ₂ for 16 h. The mixture was diluted with saturated aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100 ) To give the title compound (58.8 mg, 32% yield) as a pale yellow solid: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.77 (3H, s), 4.42 (4H, t, J = 12.6 Hz), 6.43-6.82 (1H, m), 6.90-7.49 (8H, m), 7.79 (1H, s), 8.39-8.60 (1H, m).

Reference Example 48
1- [3- (3,3-Difluoropyrrolidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- on

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (221 mg, 0.5 mmol), 3, Of 3-difluoropyrrolidine hydrochloride (86.1 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) A mixture in 1,4-dioxane (2.5 mL) was heated at 90 ° C. under N ₂ for 24 hours. The mixture was diluted with saturated aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100 ) To give the title compound (119 mg, 51% yield) as a pale yellow solid: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 2.42-2.50 (2H, m), 3.56 ( 2H, t, J = 7.4 Hz), 3.71-3.88 (5H, m), 6.43-6.54 (1H, m), 6.84-7.13 (3H, m), 7.27-7.49 (5H, m), 7.78 (1H, d. J = 1.9 Hz), 8.47 (1H, d, J = 2.3 Hz). Anal.Calcd for C ₂₄ H ₂₀ F ₃ N ₅ O ₂・ 0.2H ₂ O: C, 61.20; H, 4.37; N, 14.87. Found: C, 61.36; H, 4.45; N, 14.56.

Reference Example 49
1- {2-Fluoro-3- [3- (trifluoromethyl) pyrrolidin-1-yl] phenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H )-on

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (300 mg, 0.68 mmol), 3- (Trifluoromethyl) pyrrolidine hydrochloride (143 mg, 0.82 mmol), NaO-t-Bu (170 mg, 1.8 mmol), Xantphos (31 mg, 0.054 mmol) and Pd ₂ (dba) ₃ (12 mg, 0.014 mmol ) In 1,4-dioxane (4 mL) was heated at 90 ° C. under Ar for 14 h. The mixture was extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified by basic silica gel column chromatography (hexane / AcOEt = 10/90 to 0/100) to give the title compound ( 131 mg, 39% yield) was obtained as a white amorphous solid: ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 2.09-2.40 (2H, m), 3.05 (1H, s), 3.38-3.75 (4H, m), 3.83-3.99 (3H, m), 5.88-6.07 (1H, m), 6.65 (1H, td, J = 8.3, 1.5 Hz), 6.80-6.95 (1H, m), 7.22 (1H , d, J = 2.3 Hz), 7.30-7.49 (5H, m), 7.72 (1H, d, J = 2.6 Hz), 7.74-7.80 (1H, m); MS Calcd .: 499; MS Found: 500 [ M + H] ⁺ .

Reference Example 50
1- {2-Fluoro-4- [3- (trifluoromethyl) pyrrolidin-1-yl] phenyl} -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H )-on

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (300 mg, 0.61 mmol), 3- (Trifluoromethyl) pyrrolidine hydrochloride (130 mg, 0.74 mmol), NaO-t-Bu (154 mg, 1.6 mmol), Xantphos (28 mg, 0.049 mmol) and Pd ₂ (dba) ₃ (11 mg, 0.012 mmol ) In 1,4-dioxane (4 mL) was heated at 90 ° C. under Ar for 12 h. The mixture was extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified by basic silica gel column chromatography (hexane / AcOEt = 10/90 to 0/100) to give the title compound ( 138 mg, 45% yield) was obtained as a pale green solid: ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 2.17-2.42 (2H, m), 3.01-3.21 (1H, m), 3.30-3.63 (4H, m), 3.89 (3H, s), 6.11 (1H, dd, J = 8.9, 2.4 Hz), 6.20-6.37 (2H, m), 7.24 (1H, d, J = 1.9 Hz), 7.33- 7.47 (5H, m), 7.71 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 1.9 Hz); MS Calcd .: 499; MS Found: 500 [M + H] ⁺ .

Reference Example 51
1- [2-Fluoro-3- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (221 mg, 0.500 mmol), 3, 3,4,4-tetrafluoropyrrolidine hydrochloride (108 mg, 0.600 mmol), sodium tert-butoxide (125 mg, 1.300 mmol), Xantphos (23 mg, 0.040 mmol) and tris (dibenzylideneacetone) dipalladium (0 ) (9 mg, 0.010 mmol) in 1,4-dioxane (2.5 mL) was stirred at 90 ° C. under Ar atmosphere. The reaction mixture was poured into 5% aqueous NaHCO ₃ solution (20 mL) and extracted with AcOEt (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over MgSO ₄ and evaporated. The residue was purified by silica gel column chromatography (AcOEt / hexane = 60% -100%) to give the title compound (95.4 mg, 38% yield) as an amorphous solid: ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.84-3.96 (7H, m), 6.11 (1H, t, J = 7.5 Hz), 6.60 (1H, td, J = 8.3, 1.5 Hz), 6.90-6.98 (1H, m), 7.25 ( 1H, d, J = 1.9 Hz), 7.33-7.41 (5H, m), 7.70 (1H, d, J = 2.6 Hz), 7.78 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 504 [M + H] ⁺ .

Reference Example 52
1- (2-Fluoro-3-pyridin-3-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (3-bromo-2-fluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (177 mg, 0.400 mmol), 3- pyridineboronic acid (54.1 mg, 0.440 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.020 mmol) and _{Na 2 CO 3 (93 mg,} 0.88 mmol) in DME (3.6 mL) and water (0.9 mL) The solution was stirred at 85 ° C. for 5 hours under Ar atmosphere. The mixture was poured into 5% aqueous NaHCO ₃ solution (20 mL) and extracted with AcOEt (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over MgSO ₄ and evaporated. The residue was purified by basic silica gel column chromatography (MeOH / AcOEt = 0% -10%) and crystallized from AcOEt to give the title compound (84.8 mg, 48% yield) as a colorless solid: mp 147 -153 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 3.78 (3H, s), 7.01 (1H, d, J = 1.9 Hz), 7.04-7.17 (1H, m), 7.28-7.51 (6H, m), 7.56 (1H, dd, J = 7.7, 5.1 Hz), 7.63-7.75 (1H, m), 7.79 (1H, d, J = 1.9 Hz), 8.03 (1H, dd, J = 7.9 , 1.9 Hz), 8.58-8.68 (2H, m), 8.81 (1H, s). LC-MS (ESI) m / z 440 [M + H] ⁺ . Anal. Calcd for C ₂₅ H ₁₈ FN ₅ O ₂ : C, 68.33; H, 4.13; N, 15.94. Found: C, 68.04; H, 4.03; N, 15.80.

Reference Example 53
1- [2-Fluoro-4- (3-methyl-2-oxoimidazolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

1- [2-Fluoro-4- (2-oxoimidazolidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one A mixture of (40 mg, 0.09 mmol), iodomethane (0.02 mL, 0.36 mmol) and sodium hydride (60% oily) (7.0 mg, 0.18 mmol) in DMF (4.0 mL) was stirred at 0 ° C. for 2 hours. The reaction mixture was quenched with H ₂ O and extracted with AcOEt. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was recrystallized from ⁱ Pr ₂ O / AcOEt to give the title compound (24 mg, 59% yield) as a white solid: mp 208-209 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) : δ ppm 2.79 (3H, s), 3.42-3.58 (2H, m), 3.77 (3H, s), 3.78-3.86 (2H, m), 6.95 (1H, d, J = 1.9 Hz), 7.01 (1H , t, J = 9.0 Hz), 7.22-7.51 (6H, m), 7.73 (1H, dd, J = 14.1, 2.4 Hz), 7.78 (1H, d, J = 1.9 Hz), 8.44 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 461 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₁ FN ₆ O ₃・ 0.75H ₂ O: C, 60.06; H, 4.49; N , 18.27. Found: C, 60.05; H, 4.26; N, 18.16.

Reference Example 54
1- [4- (2,5-Dihydro-1H-pyrrol-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3- Pyrroline (0.046 mL, 0.6 mmol), Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol) and NaO-t-Bu (67.3 mg, 0.7 mmol) in 1,4-dioxane (2.5 mL) The suspension was stirred at 90 ° C. for 2 hours under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with hexane / THF (1/2)) and recrystallized from MeOH / H ₂ O to give the title compound (109 mg, 51% yield) as a yellow solid. Obtained: mp 204-207 ° C; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.89 (3H, s), 4.09 (4H, s), 5.97 (2H, t, J = 4.1 Hz), 6.07 ( 1H, dd, J = 2.6, 9.0 Hz), 6.19 (1H, dd, J = 2.6, 14.3 Hz), 6.32 (1H, t, J = 9.0 Hz), 7.24 (1H, d, J = 1.9 Hz), 7.33-7.45 (5H, m), 7.72 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 430 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₀ FN ₅ O ₂ : C, 67.12; H, 4.69; N, 16.31.Found: C, 67.03; H, 4.76; N, 16.16.

Reference Example 55
1- [4- (4-Chloro-1H-pyrazol-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (488 mg, 1.0 mmol), 4- CH ₃ CN of chloro-1H-pyrazole (103 mg, 1.0 mmol), Cu ₂ O (14.3 mg, 0.1 mmol), salicylaldoxime (54.9 mg, 0.4 mmol) and Cs ₂ CO ₃ (652 mg, 2.0 mmol) (10 mL) The suspension was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (eluted with AcOEt) followed by purification by preparative HPLC. Recrystallization from MeOH / H ₂ O gave the title compound (68.1 mg, 15% yield) as a pale yellow powder: mp 190-192 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.92 (3H, s), 6.43 (1H, t, J = 9.0 Hz), 7.23 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.35 (1H, d, J = 1.9 Hz), 7.36-7.48 ( 5H, m), 7.57 (1H, dd, J = 2.6, 12.4 Hz), 7.68 (1H, s), 7.79 (1H, d, J = 1.9 Hz), 7.82 (1H, d, J = 2.3 Hz), 7.92 (1H, d, J = 0.8 Hz). LC-MS (ESI) m / z 463 [M + H] ⁺ . Anal. Calcd for C ₂₃ H ₁₆ ClFN ₆ O ₂ : C, 59.68; H, 3.48; N, 18.16. Found: C, 59.81; H, 3.50; N, 18.14.
Preparative HPLC was performed under the following conditions.
Column: CHIRALPAK AS CC001 (50 mm ID × 500 mmL)
Column temperature: 30 ° C
Mobile phase: MeOH
Flow rate: 60 mL / min
Detector: UV 220 nm
Concentration: 111 mg / mL
Injection volume: 1 mL
Retention time: 18.8 minutes

Reference Example 56
1- [5- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on

1- (2-fluoro-5-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), 3, 3-Difluoroazetidine hydrochloride (77.7 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd ₂ (dba) ₃ (18.3 mg, 0.02 mmol) Of 1,4-dioxane (2.5 mL) was heated at 90 ° C. for 13 h under Ar. The mixture was diluted with saturated aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100 ) And recrystallized with EtOH / hexanes to give the title compound (92 mg, 41% yield) as a white solid: ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.77 (3H , s), 4.25 (4H, t, J = 12.2 Hz), 6.48 (1H, dd, J = 6.4, 3.0 Hz), 6.63-6.72 (1H, m), 6.90 (1H, d, J = 1.5 Hz) , 7.25-7.48 (6H, m), 7.79 (1H, d, J = 1.9 Hz), 8.45 (1H, d, J = 1.9 Hz). Anal. Calcd for C ₂₃ H ₁₈ F ₃ N ₅ O ₂ : C , 60.93; H, 4.00; N, 15.45.Found: C, 60.97; H, 3.94; N, 15.47.

Reference Example 57
1- [2-Fluoro-5- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

1- (2-Fluoro-5-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol), pyrazole ( 34.0 mg, 0.5 mmol), 2-hydroxybenzaldehyde oxime (27.4 mg, 0.2 mmol), Cu ₂ O (7.2 mg, 0.05 mmol) and Cs ₂ CO ₃ (326 mg, 1.0 mmol) in acetonitrile (1 mL). The mixture was heated to reflux under Ar for 14 hours. The mixture was diluted with saturated aqueous NaHCO ₃ solution, extracted with AcOEt, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and basic silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100 ) And silica gel column chromatography (hexane / AcOEt = 50/50 to 0/100) and recrystallized with AcOEt / hexane to give the title compound (8.3 mg, 4% yield) as a white solid: mp 186-187 ° C. ¹ H NMR (DMSO-d ₆ , 300 MHz): δ ppm 3.78 (3H, s), 6.59-6.66 (1H, m), 6.95 (1H, d, J = 1.9 Hz), 7.17 -7.27 (1H, m), 7.30-7.42 (4H, m), 7.56-7.67 (1H, m), 7.76-7.90 (3H, m), 7.93-8.02 (1H, m), 8.47 (1H, d, J = 2.6 Hz), 8.59 (1H, d, J = 1.9 Hz). Anal.Calcd for C ₂₃ H ₁₇ FN ₆ O ₂ : C, 64.48; H, 4.00; N, 19.62. Found: C, 64.21; H , 4.08; N, 19.42.

Reference Example 58
1- [2-Fluoro-4- (4-hydroxy-4-methylpiperidin-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H )-on

1- (2-Fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.500 mmol), 4- Methylpiperidin-4-ol hydrochloride (91 mg, 0.60 mmol), sodium tert-butoxide (187 mg, 1.95 mmol), Xantphos (23 mg, 0.040 mmol) and tris (dibenzylideneacetone) dipalladium (0) (9 mg, 0.010 mmol) of 1,4-dioxane (2.5 mL) was stirred at 90 ° C. under Ar atmosphere. The reaction mixture was poured into 5% aqueous NaHCO ₃ solution (20 mL) and extracted with AcOEt (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over MgSO ₄ and evaporated. The residue was purified by basic silica gel column chromatography (MeOH / AcOEt = 0% -20%). The residue was recrystallized from AcOEt / hexane to give the title compound (76.2 mg, 32% yield) as a pale yellow solid: ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 1.14 (3H, s ), 1.39-1.60 (4H, m), 3.20 (2H, ddd, J = 13.2, 8.7, 5.3 Hz), 3.40-3.52 (2H, m), 3.76 (3H, s), 4.36 (1H, s), 6.70 (1H, dd, J = 9.0, 2.6 Hz), 6.91 (2H, d, J = 1.9 Hz), 6.79-6.94 (1H, m), 7.29 (1H, s), 7.32 (1H, d, J = 1.9 Hz), 7.35-7.47 (3H, m), 7.77 (1H, d, J = 1.9 Hz), 8.37 (1H, d, J = 1.9 Hz). LC-MS (ESI) m / z 476 (M + H] ⁺ . Anal. Calcd for C ₂₆ H ₂₆ FN ₅ O ₃ : C, 65.67; H, 5.51; N, 14.73. Found: C, 65.53; H, 5.50; N, 14.66.

Reference Example 59
1- (4-Bromo-2,5-difluorophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-Acetyl-1- (4-bromo-2,5-difluorophenyl) -5-methoxypyridazin-4 (1H) -one (3.57 g, 10 mmol) and N, N-dimethylformamide dimethyl acetal (16 mL) The mixture was stirred at 100 ° C. for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (20 mL) and phenylhydrazine (2.0 mL, 20 mmol) was added. The mixture was stirred at 130 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with hexane / AcOEt (1/0 to 0/1)) and recrystallized from ⁱ Pr ₂ O / AcOEt to give the title compound (1.05 g, 23% yield). Obtained as a pale yellow solid: mp 211-213 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 3.77 (3H, s), 7.02 (1H, d, J = 1.9 Hz), 7.09 (1H , dd, J = 8.9, 6.6 Hz), 7.22-7.62 (5H, m), 7.80 (1H, d, J = 1.9 Hz), 8.07 (1H, dd, J = 10.2, 6.0 Hz), 8.49 (1H, d-J = 2.3 Hz). LC-MS (ESI) m / z 460 [M + H] ⁺ . Anal. Calcd for C ₂₀ H ₁₃ BrF ₂ N ₄ O ₂ : C, 52.31; H, 2.85; N, 12.20. Found: C, 52.51; H, 2.95; N, 12.20.

Reference Example 60
1- [4- (5,5-Dimethyl-2-oxo-1,3-oxazolidine-3-yl) -2-fluorophenyl] -5-methoxy-3- (1-phenyl-1H-pyrazole-5- Yl) pyridazine-4 (1H) -one

1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.500 mmol), 5, 5-Dimethyl-1,3-oxazolidine-2-one (69.1 mg, 0.600 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.100 mmol), CuI (9.5 mg, 0.050 mmol) and K ₃ PO ₄ A suspension of (212 mg, 1.00 mmol) of 1,4-dioxane (2.0 mL) was stirred at 110 ° C. under Ar atmosphere. The reaction mixture was poured into 5% aqueous NaHCO ₃ solution (20 mL) and extracted with AcOEt (20 mL × 3). The combined organic layers were washed with brine (40 mL), dried over MgSO ₄ and evaporated. The residue was purified by basic silica gel column chromatography (MeOH / AcOEt = 0% -10%) to give the title compound (157.4 mg, 66% yield): ¹ H NMR (300 MHz, DMSO-d ₆ ) : δ ppm 1.49 (6H, s), 3.78 (3H, s), 3.89 (2H, s), 6.97 (1H, d, J = 1.9 Hz), 7.05 (1H, t, J = 9.0 Hz), 7.31 ( 1H, d, J = 8.7 Hz), 7.31 (1H, t, J = 1.7 Hz), 7.33 (1H, s), 7.37-7.48 (3H, m), 7.68 (1H, dd, J = 13.4, 2.5 Hz ), 7.79 (1H, d, J = 1.9 Hz), 8.46 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 476 [M + H] ⁺ . Anal. Calcd for C ₂₅ H ₂₂ FN ₅ O ₄ : C, 63.15; H, 4.66; N, 14.73.Found: C, 63.09; H, 4.70; N, 14.85.

Reference Example 61
5-Methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-Acetyl-5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one (1.50 g, 4.41 mmol), N, N-dimethylformamide A mixture of dimethylacetal (15 mL) and MeOH (15 mL) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.
A solution of the residue and phenylhydrazine (0.868 mL, 8.82 mmol) in AcOH (15 mL) was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into 1 M hydrochloric acid and extracted with AcOEt. The extract was washed with 1 M aqueous NaOH and brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluting with AcOEt) and crystallized from hexane / AcOEt to give the title compound (0.921 g, 47% yield) as an off-white solid: mp 133-135 ° C ; ¹ H NMR (300 MHz, CDCl ₃ ): δ ppm 3.90 (3H, s), 3.93 (3H, s), 6.39 (1H, d, J = 8.7 Hz), 6.52 (1H, dd, J = 1.9, 2.6 Hz), 6.99 (1H, dd, J = 2.3, 8.7 Hz), 7.26 (1H, d, J = 1.9 Hz), 7.36-7.46 (5H, m), 7.49 (1H, d, J = 2.3 Hz) , 7.75 (1H, d, J = 1.9 Hz), 7.77 (1H, d, J = 1.9 Hz), 7.86 (1H, s), 7.94 (1H, d, J = 2.6 Hz). LC-MS (ESI) m / z 441 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₀ N ₆ O ₃ : C, 65.45; H, 4.58; N, 19.08. Found: C, 65.37; H, 4.65; N, 18.88.

Reference Example 62
1- (2,3-Difluoro-4-morpholin-4-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-acetyl-1- (2,3-difluoro-4-morpholin-4-ylphenyl) -5-methoxypyridazin-4 (1H) -one (200 mg, 0.55 mmol) and N, N-dimethylformamide dimethyl acetal (2.0 mL) was stirred at 120 ° C. for 2.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (2.0 mL), and phenylhydrazine (0.11 mL, 1.1 mmol) was added. The mixture was stirred at room temperature for 1 hour and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with AcOEt / MeOH (1/0 to 10/1)) and recrystallized from ⁱ Pr ₂ O / AcOEt to give the title compound (141 mg, 55% yield). Obtained as a yellow solid: mp 182-183 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 2.98-3.22 (4H, m), 3.62-3.87 (7H, m), 6.78-6.92 (2H , m), 6.95 (1H, d, J = 1.9 Hz), 7.21-7.54 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 8.48 (1H, d, J = 1.9 Hz). LC -MS (ESI) m / z 466 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₁ F ₂ N ₅ O ₃ : C, 61.93; H, 4.55; N, 15.05. Found: C, 61.90; H , 4.58; N, 14.87.

Reference Example 63
1- (2,5-Difluoro-4-morpholin-4-ylphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

3-acetyl-1- (2,5-difluoro-4-morpholin-4-ylphenyl) -5-methoxypyridazin-4 (1H) -one (340 mg, 0.93 mmol) and N, N-dimethylformamide dimethyl acetal (3.4 mL) was stirred at 120 ° C. for 2.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in AcOH (3.4 mL), and phenylhydrazine (0.18 mL, 1.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with AcOEt and washed with saturated aqueous NaHCO ₃ and brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was recrystallized from AcOEt / MeOH to give the title compound (156 mg, 36% yield) as a pale solid: mp 211-212 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ ppm 2.99-3.15 (4H, m), 3.60-3.88 (7H, m), 6.85 (1H, dd, J = 12.8, 7.2 Hz), 6.99 (1H, d, J = 2.3 Hz), 7.09 (1H, dd, J = 12.8, 7.6 Hz), 7.24-7.50 (5H, m), 7.79 (1H, d, J = 1.9 Hz), 8.43 (1H, d, J = 2.3 Hz). LC-MS (ESI) m / z 466 [M + H] ⁺ . Anal. Calcd for C ₂₄ H ₂₁ F ₂ N ₅ O ₃・ 0.5H ₂ O: C, 60.75; H, 4.67; N, 14.76. Found: C, 60.98; H, 4.71; N, 14.63.

Reference Example 64
1- (1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1-Benzyl-4- [4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] pyridinium bromide
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1-pyridin-4-ylpyridazin-4 (1H) -one (0.49 g) and benzyl bromide (0.25 mL) were added to acetonitrile (30 (mL) and heated to reflux overnight. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (0.73 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.90 (3H, s), 5.76 (2H, s), 7.26 (1H, d, J = 1.9 Hz), 7.37-7.52 (10H, m), 7.79 ( 2H, d, J = 7.4 Hz), 7.86 (1H, d, J = 1.9 Hz), 8.72 (1H, s), 9.15 (2H, d, J = 7.4 Hz).
B) 1- (1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on
Boron in methanol (30 mL) solution of 1-benzyl-4- [4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] pyridinium bromide (0.73 g) Sodium hydride (0.21 g) was added at 0 ° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate and recrystallized from ethyl acetate to give the title compound (0.15 g).
MS (ESI +), found: 440.2

Reference Example 65
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- (1-prop-2-en-1-yl-1,2,3,6-tetrahydropyridin-4-yl) Pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Reference Example 64.
MS (ESI +), found: 390.2

Reference Example 66
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1-piperidin-4-ylpyridazin-4 (1H) -one
1- (1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one To a methanol solution (25 mL) of (1.3 g), palladium hydroxide carbon (10% wet, 0.40 g) was added. The reaction mixture was stirred at 50 ° C. for 4 hours under hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / methanol) and crystallized from 2-propanol / heptane to give the title compound (0.41 g).
MS (ESI +), found: 352.1

Reference Example 67
1- [1- (4-Fluorophenyl) piperidin-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1-piperidin-4-ylpyridazin-4 (1H) -one (150 mg), 1-bromo-4-fluorobenzene (0.094 suspension of dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphane (21 mg) and sodium tert-butoxide (61 mg) in toluene (8 mL) Was stirred at 120 ° C. for 8 hours under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to give the title compound (12 mg).
MS (ESI +), found: 446.2

Reference Example 68
2- {4- [5-methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] piperidin-1-yl} benzonitrile Reference Example 67 and The title compound was obtained in a similar manner.
MS (ESI +), found: 453.2

Reference Example 69
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- (1,2,3,6-tetrahydropyridin-4-yl) pyridazin-4 (1H) -one
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- (1-prop-2-en-1-yl-1,2,3,6-tetrahydropyridin-4-yl) A suspension of pyridazine-4 (1H) -one (1.5 g), tetrakis (triphenylphosphine) palladium (0) (500 mg) and 1,3-dimethylbarbituric acid (1.8 g) in toluene (30 mL) The mixture was heated to reflux for 8 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and recrystallized from acetonitrile to give the title compound (0.28 g).
MS (ESI +), found: 350.2

Reference Example 70
1- [1- (2,3-Difluorophenyl) piperidin-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one Reference Example 67 The title compound was obtained in a similar manner to
MS (ESI +), found: 464.2

Reference Example 71
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [1- (1,3-thiazol-2-yl) piperidin-4-yl] pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Reference Example 67.
MS (ESI +), found: 435.1

Reference Example 72
1- [1- (3-Chloropyridin-2-yl) piperidin-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one Reference The title compound was obtained in the same manner as in Example 67.
MS (ESI +), found: 463.1

Reference Example 73
2- {4- [5-Methoxy-4-oxo-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-1 (4H) -yl] piperidin-1-yl} pyridine-3-carbonitrile The title compound was obtained in the same manner as in Reference Example 67.
MS (ESI +), found: 454.1

Reference Example 74
1- (3'-Chloro-3,6-dihydro-2H-1,2'-bipyridin-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -one The title compound was obtained in the same manner as in Reference Example 67.
MS (ESI +), found: 461.0

  The structural formulas of the compounds obtained in Reference Examples 64-74 are shown in Tables 1-1 to 1-3 below.

Reference Example 75 and Reference Example 76
1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -On (Reference Example 75)
5-Methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -On (Reference Example 76)
3-acetyl-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (300 mg), N, N-dimethylacetamidodimethylacetal ( After stirring a mixture of 3 mL) and acetonitrile (3 mL) at 80 ° C. for 12 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in acetic acid (5 mL), and phenylhydrazine (98.8 mg) was added at room temperature. The reaction mixture was stirred at 80 ° C. for 3 hours, and the solvent was evaporated under reduced pressure. The mixture was treated with 1 M hydrochloric acid, the residue was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give 1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (3-methyl-1- Phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (69 mg) and 5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- A mixture containing (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one was obtained. The resulting mixture was purified by preparative HPLC to give 5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (3-methyl-1-phenyl-1H-pyrazole -5-yl) pyridazin-4 (1H) -one (28 mg) was obtained.
1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on:
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (3H, s), 3.78 (3H, s), 6.59-6.66 (1H, m), 6.79 (1H, s), 7.08-7.21 (1H, m ), 7.25-7.49 (5H, m), 7.74 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 1.5 Hz), 7.91-8.04 (1H, m), 8.52 (1H, d, J = 1.9 Hz), 8.66 (1H, d, J = 2.7 Hz).
5-Methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -on:
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.29 (3H, s), 3.76 (3H, s), 3.91 (3H, s), 6.60 (1H, s), 6.75 (1H, s), 6.93 ( 1H, d, J = 8.7 Hz), 7.20-7.49 (6H, m), 7.64 (1H, d, J = 1.9 Hz), 7.80 (1H, s), 8.38 (1H, s), 8.66 (1H, d , J = 2.7 Hz).

Reference Example 77
3- [1- (3-Chloro-2-fluorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine -4 (1H) -ON
A) 3- [3- (Dimethylamino) prop-2-enoyl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one
3-acetyl-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (600 mg) and N, N-dimethylformamide dimethyl acetal ( A mixture of 3 mL) and acetonitrile (3 mL) was stirred at 80 ° C. for 12 hours, cooled to room temperature, and further stirred for 12 hours. The precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (600 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.82 (3H, s), 3.09 (3H, s), 3.79 (3H, s), 5.25 (1H, brs), 6.64 (1H, dd, J = 2.5 , 1.8 Hz), 7.51 (1H, brs), 7.79-7.95 (3H, m), 7.99-8.10 (1H, m), 8.50 (1H, d, J = 1.8 Hz), 8.68 (1H, d, J = 2.5 Hz).
B) 3- [1- (3-Chloro-2-fluorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5- Methoxypyridazine-4 (1H) -one
3- [3- (Dimethylamino) prop-2-enoyl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (200 (3-Chloro-2-fluorophenyl) hydrazine hydrochloride (98.8 mg) was added to a solution of mg) in trifluoroacetic acid / ethanol (5/95, 8 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (97 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (3H, s), 6.57-6.71 (1H, m), 7.12-7.22 (1H, m), 7.23-7.32 (1H, m), 7.38- 7.49 (2H, m), 7.55-7.69 (1H, m), 7.72-7.81 (1H, m), 7.81-8.01 (3H, m), 8.50 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 2.6 Hz).

Reference Example 78
3- [1- (5-Chloro-2-fluorophenyl) -1H-pyrazol-5-yl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazine -4 (1H) -ON
3- [3- (Dimethylamino) prop-2-enoyl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (200 (5-Chloro-2-fluorophenyl) hydrazine hydrochloride (88.8 mg) was added to a solution of mg) in trifluoroacetic acid / ethanol (5/95, 8 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (98 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.80 (3H, s), 6.52-6.71 (1H, m), 7.10-7.26 (1H, m), 7.27-7.41 (2H, m), 7.45-7.54 (1H, m), 7.60-7.68 (1H, m), 7.74-7.81 (1H, m), 7.82-7.90 (2H, m), 7.92-8.00 (1H, m), 8.51 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 2.6 Hz).

Reference Example 79
1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- {1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-5-yl} pyridazine -4 (1H) -ON
3- [3- (Dimethylamino) prop-2-enoyl] -1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (200 [3- (Trifluoromethyl) phenyl] hydrazine (96.5 mg) was added to a solution of mg) in trifluoroacetic acid / EtOH (5/95, 8 mL) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (185 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.79 (3H, s), 6.63 (1H, s), 7.11 (1H, s), 7.30-7.44 (1H, m), 7.56-7.82 (5H, m ), 7.80-7.92 (2H, m), 7.93-8.04 (1H, m), 8.56 (1H, s), 8.66 (1H, d, J = 2.3 Hz).

Reference Example 80
1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- {1- [3- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl} pyridazine -4 (1H) -ON
A) [3- (Trifluoromethoxy) phenyl] hydrazine hydrochloride
3- (Trifluoromethoxy) aniline (3.68 ml) is dissolved in 6 M hydrochloric acid (71 ml), and an aqueous solution (4.7 ml) of sodium nitrite (2.08 g) is added dropwise at -5 ° C over 20 minutes. It was. A solution of tin (II) chloride (1.954 ml) in 6 M hydrochloric acid (25 ml) was added to the mixture at -5 ° C. After stirring at −5 ° C. for 2 hours, the precipitated solid was collected by filtration, washed with 0.1M hydrochloric acid and dried under reduced pressure to obtain the title compound (2.72 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.81-7.03 (3H, m), 7.41 (1H, t, J = 8.3 Hz), 8.64 (1H, brs), 10.35 (2H, brs).
B) 1- [2-Fluoro-4- (1H-pyrazol-1-yl) phenyl] -5-methoxy-3- {1- [3- (trifluoromethoxy) phenyl] -1H-pyrazol-5-yl } Pyridazine-4 (1H) -one
3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [2-fluoro-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one (200 mg) in ethanol (2.0 mL) was added dropwise with a solution of [3- (trifluoromethoxy) phenyl] hydrazine hydrochloride (139 mg) and trifluoroacetic acid (0.2 mL) in ethanol (2.0 mL) at room temperature. Stir for 24 hours. An ethanol solution (0.3 ml) of [3- (trifluoromethoxy) phenyl] hydrazine hydrochloride (16.7 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The precipitated solid was collected by filtration. The mother liquor was concentrated and the precipitated solid was collected by filtration and combined with the first obtained solid and recrystallized from acetone / water to give the title compound (96.1 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.79 (3H, s), 6.64 (1H, d, J = 2.6 Hz), 7.03 (1H, d, J = 1.9 Hz), 7.27-7.49 (4H, m) , 7.57 (1H, t, J = 8.1 Hz), 7.74-7.88 (3H, m), 7.99 (1H, dd, J = 12.1, 2.3 Hz), 8.57 (1H, d, J = 1.9 Hz), 8.66 ( (1H, d, J = 2.6 Hz).
mp 148-150 ℃
Anal. Calcd for C ₂₄ H ₁₆ F ₄ N ₆ O ₃ -0.5H ₂ O: C, 55.28; H, 3.29; N, 16.11. Found: C, 55.25; H, 3.07; N, 16.05.

Reference Example 81
5-Methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- {1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-5-yl} pyridazine -4 (1H) -ON
A) 3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one
3-acetyl-5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one (264 mg), N, N-dimethylformamide dimethyl acetal ( A mixture of 1.5 mL) and acetonitrile (1.5 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (274 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.90 (3H, s), 3.12 (3H, s), 3.89 (3H, s), 3.97 (3H, s), 5.89 (1H, brs), 6.52 (1H, dd, J = 2.6, 1.9 Hz), 7.26 (1H, dd, J = 8.3, 2.3 Hz), 7.59 (1H, d, J = 1.9 Hz), 7.63 (1H, d, J = 8.7 Hz), 7.76 ( 1H, d, J = 1.9 Hz), 7.79 (1H, brs), 7.82 (1H, s), 7.98 (1H, d, J = 2.3 Hz).
B) 5-Methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] -3- {1- [3- (trifluoromethyl) phenyl] -1H-pyrazol-5-yl } Pyridazine-4 (1H) -one
3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one (136 To a suspension of mg) in ethanol (1.5 mL), a solution of 3- (trifluoromethyl) phenylhydrazine (0.049 mL) in trifluoroacetic acid (0.15 mL) in ethanol (1.5 mL) was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, ethyl acetate), and recrystallized from ethanol / water to give the title compound (123 mg).
mp 215-217 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.89 (3H, s), 3.93 (3H, s), 6.53 (1H, dd, J = 2.6, 1.9 Hz), 6.62 (1H, d, J = 8.7 Hz) , 7.03 (1H, dd, J = 8.7, 2.3 Hz), 7.30 (1H, d, J = 1.9 Hz), 7.48-7.53 (2H, m), 7.57-7.62 (2H, m), 7.67-7.68 (1H , m), 7.76 (1H, d, J = 1.5 Hz), 7.80 (1H, d, J = 1.9 Hz), 7.82 (1H, s), 7.93 (1H, d, J = 2.3 Hz).
Anal. Calcd for C ₂₅ H ₁₉ F ₃ N ₆ O ₃ : C, 59.06; H, 3.77; N, 16.53.Found: C, 58.97; H, 3.85; N, 16.40.

Reference Example 82
3- [1- (3-Chlorophenyl) -1H-pyrazol-5-yl] -5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazine-4 (1H) -on
3- [3- (Dimethylamino) prop-2-enoyl] -5-methoxy-1- [2-methoxy-4- (1H-pyrazol-1-yl) phenyl] pyridazin-4 (1H) -one (136 mg) in ethanol (1.5 mL) was added dropwise a solution of 3-chlorophenylhydrazine hydrochloride (67.7 mg) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate), crystallized from ethyl acetate, and recrystallized from ethanol / water to give the title compound (68.0 mg). .
mp 167-168 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.90 (3H, s), 3.95 (3H, s), 6.53 (1H, dd, J = 2.6, 1.9 Hz), 6.68 (1H, d, J = 8.7 Hz) , 7.08 (1H, dd, J = 8.7, 2.3 Hz), 7.27-7.36 (4H, m), 7.44-7.45 (1H, m), 7.53 (1H, d, J = 2.3 Hz), 7.76 (1H, d , J = 1.9 Hz), 7.77 (1H, d, J = 1.9 Hz), 7.84 (1H, s), 7.96 (1H, d, J = 2.6 Hz).
Anal. Calcd for C ₂₄ H ₁₉ ClN ₆ O ₃ : C, 60.70; H, 4.03; N, 17.70. Found: C, 60.73; H, 4.08; N, 17.58.

Reference Example 83
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -ON
A) 4-Bromo-2- (tert-butoxy) -1-nitrobenzene
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25.2 g) in THF (250 mL) was added potassium tert-butoxide (25.3 g) little by little at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (28.6 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44 (9H, s), 7.26 (1H, dd, J = 8.7, 2.3 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 8.7 Hz).
[0394]
B) 1- (3-tert-Butoxy-4-nitrophenyl) -3,4-difluoro-1H-pyrrole
4-Bromo-2- (tert-butoxy) -1-nitrobenzene (13.7 g), 3,3,4,4-tetrafluoropyrrolidine hydrochloride (9.87 g), Pd ₂ (dba) ₃ (0.916 g), Xantphos A suspension of (2.31 g) and sodium tert-butoxide (19.2 g) in 1,4-dioxane (150 mL) was stirred at 90 ° C. for 4 hours under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) and recrystallized from hexane / ethyl acetate to give the title compound (8.35 g).
¹ H NMR (300 MHZ, CDCl ₃ ) δ 1.47 (9H, s), 6.72-6.82 (2H, m), 7.00 (1H, dd, J = 8.7, 2.6 Hz), 7.04 (1H, d, J = 2.6 Hz), 7.88 (1H, d, J = 8.7 Hz).

C) 5- (3,4-Difluoro-1H-pyrrol-1-yl) -2-nitrophenol
A mixture of 1- (3-tert-butoxy-4-nitrophenyl) -3,4-difluoro-1H-pyrrole (8.30 g), trifluoroacetic acid (30 mL) and tetrahydrofuran (60 mL) was heated to reflux for 3 hours. . The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane / ethyl acetate (10/1) to obtain the title compound (6.43 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.80-6.91 (3H, m), 6.98 (1H, d, J = 2.6 Hz), 8.18 (1H, d, J = 9.4 Hz), 10.85 (1H, s) .

D) 1- [3- (Benzyloxy) -4-nitrophenyl] -3,4-difluoro-1H-pyrrole
5- (3,4-Difluoro-1H-pyrrol-1-yl) -2-nitrophenol (6.39 g), benzyl bromide (3.48 mL) and potassium carbonate (5.51 g) in N, N-dimethylformamide (60 mL) The suspension was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane / ethyl acetate to give the title compound (8.57 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.30 (2H, s), 6.67-6.77 (2H, m), 6.88-6.92 (2H, m), 7.33-7.51 (5H, m), 8.02 (1H, d , J = 8.3 Hz).

E) 2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) aniline in a mixture of zinc (33.7 g), tetrahydrofuran (40 mL) and acetic acid (80 mL) A mixture of 3- (benzyloxy) -4-nitrophenyl] -3,4-difluoro-1H-pyrrole (8.52 g), tetrahydrofuran (80 mL) and acetic acid (40 mL) was added dropwise at 0 ° C. Stir for 15 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) and recrystallized from hexane / ethyl acetate to give the title compound (7.53 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.86 (2H, s), 5.10 (2H, s), 6.50-6.60 (2H, m), 6.69-6.76 (3H, m), 7.33-7.46 (5H, m ).

F) 2-{[2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] hydrazono} -4-methoxy-3-oxobutanoate methyl
A mixture of 2- (benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) aniline (7.51 g) and 6M hydrochloric acid (50 mL) was added sodium nitrite (3.45 g) in water (10 mL) The solution was added dropwise at 0 ° C. and stirred for 15 minutes. The reaction mixture was added to a suspension of methyl 4-methoxyacetoacetate (3.24 mL) and sodium acetate (24.6 g) in methanol (50 mL) cooled to 0 ° C. The reaction mixture was stirred for 15 minutes, poured into water, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane / ethyl acetate and recrystallized from hexane / tetrahydrofuran to give the title compound (4.87 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.51 (3H, s), 3.90 (3H, s), 4.68 (2H, s), 5.27 (2H, s), 6.59-6.69 (2H, m), 6.87 ( 1H, d, J = 2.3 Hz), 6.94 (1H, dd, J = 8.7, 2.3 Hz), 7.34-7.52 (5H, m), 7.61 (1H, d, J = 8.7 Hz), 13.27 (1H, s ).

G) 1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid Methyl acid
2-{[2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] hydrazono} -4-methoxy-3-oxobutanoate (4.85 g) and N, N A mixture of -dimethylformamide dimethylacetal (100 mL) was heated to reflux for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from methanol to give the title compound (4.57 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.64 (3H, s), 3.97 (3H, s), 5.17 (2H, s), 6.69-6.79 (2H, m), 6.99-7.03 (2H, m), 7.32-7.43 (5H, m), 7.59-7.62 (1H, m), 7.80 (1H, s).

H) 1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid acid
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.54 g), a 1M aqueous sodium hydroxide solution (15 mL), a mixture of tetrahydrofuran (30 mL) and methanol (30 mL) were stirred at room temperature for 30 minutes. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitate was collected by filtration and washed with water to give the title compound (0.5 tetrahydrofuranate, 4.70 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.78 (3H, s), 5.32 (2H, s), 7.31-7.45 (6H, m), 7.59 (1H, d, J = 2.3 Hz), 7.69- 7.71 (3H, m), 8.89 (1H, s), 15.18 (1H, brs).

I) 1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4- Dihydropyridazine-3-carboxamide
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid ( 0.5 Tetrahydrofuranate, 4.67 g), N, O-dimethylhydroxylamine hydrochloride (1.11 g), WSC (2.19 g), HOBt (1.54 g) and triethylamine (1.59 mL) in N, N-dimethylformamide (75 mL) The suspension was stirred at room temperature for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, tetrahydrofuran) and recrystallized from hexane / tetrahydrofuran to give the title compound (4.51 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.38 (3H, s), 3.62 (3H, s), 3.67 (3H, s), 5.17 (2H, s), 6.69-6.79 (2H, m), 6.97- 7.01 (2H, m), 7.32-7.44 (5H, m), 7.59-7.64 (1H, m), 7.86 (1H, s).

J) 3-acetyl-1- [2- (benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine To a solution of -3-carboxamide (4.47 g) in tetrahydrofuran (270 mL) was added dropwise 1M methylmagnesium bromide in tetrahydrofuran (27 mL) at -78 ° C, and the mixture was stirred for 15 minutes. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with tetrahydrofuran and recrystallized from methanol to give the title compound (3.75 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.68 (3H, s), 3.63 (3H, s), 5.18 (2H, s), 6.71-6.81 (2H, m), 7.00-7.04 (2H, m), 7.32-7.44 (5H, m), 7.59-7.62 (1H, m), 7.80 (1H, s).

K) 1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5- Methoxypyridazine-4 (1H) -one
3-acetyl-1- [2- (benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxypyridazin-4 (1H) -one (3.70 g), A mixture of N, N-dimethylformamide dimethylacetal (40 mL) and acetonitrile (40 mL) was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (3.85 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.78 (3H, brs), 3.05 (3H, brs), 3.65 (3H, s), 5.26 (1H, brs), 5.31 (2H, s), 7.30- 7.47 (6H, m), 7.54 (1H, d, J = 2.3 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.66 (2H, d, J = 1.5 Hz), 8.40 (1H, s).

L) 1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl Pyridazine-4 (1H) -one
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -3- [3- (dimethylamino) prop-2-enoyl] -5-methoxypyridazine A solution of -4 (1H) -one (3.80 g) and phenylhydrazine (1.48 mL) in acetic acid (30 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH, ethyl acetate), crystallized from hexane / ethyl acetate, and recrystallized from dimethyl sulfoxide / ethanol to give the title compound (3.29 g). Got.
mp 221-223 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.57 (3H, s), 5.10 (2H, s), 6.31 (1H, d, J = 8.7 Hz), 6.65-6.75 (3H, m), 6.92 (1H, d, J = 2.3 Hz), 7.27-7.46 (11H, m), 7.78 (1H, d, J = 2.3 Hz), 7.88 (1H, s).
Anal. Calcd for C ₃₁ H ₂₃ F ₂ N ₅ O ₃ : C, 67.51; H, 4.20; N, 12.70. Found: C, 67.48; H, 4.27; N, 12.62.

Reference Example 84
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-methoxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON
A) 1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-hydroxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON
1- [2- (Benzyloxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine A suspension of -4 (1H) -one (3.20 g) and 10% palladium on carbon (3.20 g) in acetic acid (100 mL) was stirred at room temperature for 3 hours in a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to supercritical fluid chromatography (column: CHIRALPAK ADH (trade name), 20 mmID × 250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide / 2-propanol / acetonitrile = 700/150 / 150 (v / v / v)). Crystallization from acetone gave the title compound (1.24 g).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.75 (3H, s), 6.80 (1H, d, J = 8.7 Hz), 6.90-6.99 (2H, m), 7.02 (1H, d, J = 2.3 Hz), 7.29-7.49 (7H, m), 7.78 (1H, d, J = 1.9 Hz), 8.35 (1H, s), 10.90 (1H, brs).
B) 1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-methoxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-hydroxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( A suspension of 1H) -one (231 mg), iodomethane (0.0375 mL) and potassium carbonate (138 mg) in N, N-dimethylformamide (2.5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, tetrahydrofuran) and recrystallized from methanol / water to give the title compound (232 mg).
mp 206-207 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.89 (6H, s), 6.36 (1H, d, J = 8.7 Hz), 6.65-6.77 (3H, m), 6.81 (1H, d, J = 2.3 Hz) , 7.25 (1H, d, J = 1.9 Hz), 7.35-7.46 (5H, m), 7.77 (1H, d, J = 1.9 Hz), 7.81 (1H, s).
Anal. Calcd for C ₂₅ H ₁₉ F ₂ N ₅ O ₃ : C, 63.15; H, 4.03; N, 14.73. Found: C, 62.96; H, 3.98; N, 14.66.

Reference Example 85
1- [2- (Difluoromethoxy) -4- (3,4-difluoro-1H-pyrrol-1-yl) phenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -ON
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-hydroxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( A mixture of 1H) -one (231 mg), sodium chlorodifluoroacetate (152 mg), potassium carbonate (104 mg), N, N-dimethylformamide (2.5 mL) and water (0.5 mL) was heated to reflux overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) and crystallized from hexane / ethyl acetate to give the title compound (193 mg).
mp 168-170 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.89 (3H, s), 6.41 (1H, t, J = 72.0 Hz), 6.56 (1H, d, J = 8.7 Hz), 6.69-6.79 (2H, m) , 6.99 (1H, dd, J = 8.7, 2.6 Hz), 7.12 (1H, d, J = 2.6 Hz), 7.25 (1H, d, J = 1.9 Hz), 7.34-7.46 (5H, m), 7.74 ( 1H, s), 7.78 (1H, d, J = 1.9 Hz).
Anal. Calcd for C ₂₅ H ₁₇ F ₄ N ₅ O ₃ : C, 58.71; H, 3.35; N, 13.69. Found: C, 58.68; H, 3.41; N, 13.55.

Reference Example 86
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2- (2,2,2-trifluoroethoxy) phenyl] -5-methoxy-3- (1-phenyl-1H- Pyrazol-5-yl) pyridazine-4 (1H) -one
1- [4- (3,4-Difluoro-1H-pyrrol-1-yl) -2-hydroxyphenyl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -one (138 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (104 mg) and potassium carbonate (82 mg) in N, N-dimethylformamide (1.5 mL) suspension at room temperature Stir for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, tetrahydrofuran) and crystallized from methanol to give the title compound (131 mg).
mp 220-222 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.86 (3H, s), 4.41 (2H, q, J = 7.9 Hz), 6.37-6.41 (1H, m), 6.67-6.80 (4H, m), 7.28 ( 1H, d, J = 1.9 Hz), 7.35-7.47 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 7.83 (1H, s).
Anal. Calcd for C ₂₆ H ₁₈ F ₅ N ₅ O ₃ : C, 57.46; H, 3.34; N, 12.89. Found: C, 57.38; H, 3.38; N, 12.83.

Reference Example 87
5-methoxy-1- [2-methoxy-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON
A) 3-Acetyl-1- (4-iodo-2-methoxyphenyl) -5-methoxypyridazin-4 (1H) -one
Add 1M to a solution of 1- (4-iodo-2-methoxyphenyl) -N, 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (8.90 g) in tetrahydrofuran (150 mL). Methyl magnesium bromide tetrahydrofuran solution (30 mL) was added dropwise at −78 ° C., and the mixture was stirred for 20 minutes. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate and recrystallized from methanol / water to give the title compound (5.12 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.66 (3H, s), 3.87 (3H, s), 3.90 (3H, s), 7.21 (1H, d, J = 8.3 Hz), 7.40 (1H, d, J = 1.9 Hz), 7.47 (1H, dd, J = 8.3, 1.9 Hz), 7.71 (1H, s).
B) 1- (4-Iodo-2-methoxyphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
3-acetyl-1- (4-iodo-2-methoxyphenyl) -5-methoxypyridazin-4 (1H) -one (2.00 g), N, N-dimethylformamide dimethyl acetal (10 mL) and acetonitrile (10 mL ) Was heated to reflux for 8 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure.
To a solution of the obtained residue in ethanol (20 mL), a solution of phenylhydrazine (0.541 mL) and trifluoroacetic acid (0.743 mL) in ethanol (5 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethanol / water to give the title compound (1.36 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.84 (3H, s), 3.88 (3H, s), 5.98 (1H, d, J = 8.3 Hz), 7.13 (1H, dd, J = 8.3, 1.9 Hz) , 7.25-7.28 (2H, m), 7.34-7.45 (5H, m), 7.77 (1H, d, J = 1.9 Hz), 7.79 (1H, s).
C) 5-Methoxy-1- [2-methoxy-4- (3,3,4,4-tetrafluoropyrrolidin-1-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) Pyridazine-4 (1H) -one
1- (4-Iodo-2-methoxyphenyl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (186 mg), 3,3,4 , 4-Tetrafluoropyrrolidine hydrochloride (80.0 mg), Pd ₂ (dba) ₃ (6.8 mg), Xantphos (17.4 mg) and sodium tert-butoxide (93.0 mg) in 1,4-dioxane (2 mL) suspension The solution was stirred at 90 ° C. for 30 minutes under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (NH, ethyl acetate), and fractionated by HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (5% ammonium acetate-containing system)). The obtained fraction was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol / water to give the title compound (41.1 mg).
mp 209-213 ℃
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.76-3.93 (10H, m), 5.91 (1H, dd, J = 8.7, 2.6 Hz), 6.00 (1H, d, J = 2.6 Hz), 6.31 (1H, d, J = 8.7 Hz), 7.19 (1H, d, J = 1.9 Hz), 7.31-7.45 (5H, m), 7.73 (1H, s), 7.76 (1H, d, J = 1.9 Hz).
Anal. Calcd for C ₂₅ H ₂₁ F ₄ N ₅ O ₃ : C, 58.25; H, 4.11; N, 13.59. Found: C, 58.24; H, 4.10; N, 13.62.

Reference Example 88
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- (1,3-thiazol-2-yl) pyridazin-4 (1H) -one
A) 1-Benzyl-3-chloro-5-methoxypyridazin-4 (1H) -one
3-Chloro-5-methoxypyridazin-4-ol (10.0 g) was dissolved in DMF (300 mL), and NaH (3.26 g, 55 wt%) and n-Bu ₄ NI (4.60 g) were added at 0 ° C. After the mixture was stirred at 0 ° C. for 10 minutes, benzyl bromide (12.3 g) was added at 0 ° C. The reaction mixture was stirred at room temperature for 20 hours, then diluted with water and extracted with CH ₂ Cl ₂ . The collected organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under filtration and reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (19.8 g) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.82 (3H, s), 5.31 (2H, s), 7.34-7.42 (5H, m), 7.89 (1H, s).
B) 1-Benzyl-5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one 1-Benzyl- in toluene (330 mL) and water (33.0 mL) 3-Chloro-5-methoxypyridazin-4 (1H) -one (13.6 g), 1-phenyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) A mixture of -1H-pyrazole (22.0 g), potassium carbonate (51.0 g) and PdCl ₂ {Pt-Bu ₂ (Ph-p-NMe ₂ )} ₂ (1.92 g) was heated to reflux under a nitrogen atmosphere for 24 hours. . The reaction mixture was diluted with water and saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under filtration and reduced pressure. The residue was purified by recrystallization from ethyl acetate / hexane to give the title compound (15.1 g) as a single yellow solid.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.81 (3H, s), 5.10 (2H, s), 6.95 (1H, d, J = 1.6 Hz), 7.05-7.07 (2H, m), 7.24- 7.38 (8H, m), 7.74 (1H, d, J = 1.6 Hz), 8.33 (1H, s).
C) 5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4-ol
1-Benzyl-5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (15.0 g) and Pd in THF (500 mL) and methanol (300 mL) A mixture of (OH) ₂ / C (5.88 g, 50% water wet product) was stirred at room temperature under a hydrogen atmosphere for 2 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in ethanol / hexane, and the title compound (9.10 g) was obtained as a brown solid by filtration.
MS (ESI +): [M + H] + 269.2.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.74 (3H, s), 6.79 (1H, d, J = 1.6 Hz), 7.27-7.40 (5H, m), 7.76 (1H, d, J = 2.0 Hz),
8.15 (1H, s), 13.4 (1H, brs).
D) 5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- (1,3-thiazol-2-yl) pyridazin-4 (1H) -one
5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4-ol (70 mg), 2-chloro-1,3-thiazole (62 mg) and DMF (2 mL) A mixture of cesium carbonate (255 mg) was stirred at 100 ° C. for 12 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (44 mg).
MS (API +): [M + H] ⁺ 352.3

Reference Example 89
1- (1-Benzyl-1H-pyrazol-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) propan-2-ol
To a THF solution (450 ml) of 1-phenylpyrazole (15 g), a 1.6 M butyllithium / hexane solution was added at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. To the reaction mixture, 2- (methoxymethyl) oxirane (27.8 ml) was added at -78 ° C, and the mixture was warmed to room temperature and stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (12.2 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 2.33 (1H, d, J = 4.1 Hz), 2.88 (2H, dd, J = 6.6, 3.2 Hz), 3.19-3.28 (1H, m), 3.33 (3H, s), 3.34-3.40 (1H, m), 3.94-4.06 (1H, m, J = 10.0, 6.8, 3.4, 3.4 Hz), 6.30-6.38 (1H, m), 7.34-7.53 (5H, m), 7.63 (1H, s).
B) 1-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) propan-2-one
To a THF solution (100 ml) of DMSO (14.2 ml), trifluoroacetic anhydride was added dropwise at -42 ° C over 15 minutes, and the mixture was stirred at -42 ° C for 15 minutes. To the reaction mixture, a THF solution (66 ml) of 1-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) propan-2-ol (9.3 g) was added dropwise at -42 ° C over 1 hour, Stir at 0 ° C. for 15 minutes. Triethylamine (22.3 ml) was added dropwise to the reaction mixture at 0 ° C over 15 minutes, and the mixture was stirred at 0 ° C for 1 hour. A 10% aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.11 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 3.33 (3H, s), 3.88 (2H, s), 3.95 (2H, s), 6.34 (1H, d, J = 1.9 Hz), 7.35-7.52 (5H, m), 7.66 (1H, d, J = 1.9 Hz).
C) 1- (1-Benzyl-1H-pyrazol-4-yl) -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
To a mixture of 1-benzyl-1H-pyrazol-4-amine (75 mg) and 6M hydrochloric acid (1 mL), a solution of sodium nitrite (24 mg) in water (0.5 mL) was added dropwise at 0 ° C. and stirred for 30 minutes. . The resulting aqueous solution was cooled to 0 ° C. and 1-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) propan-2-one (100 mg) and sodium acetate (354 mg) in methanol (2 mL ) Added to suspension. The reaction mixture was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (2 mL), and N, N-dimethylformamide dimethyl acetal (0.3 mL) was added. The reaction mixture was stirred at 80 ° C. for 12 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (11 mg).
MS (API +): [M + H] ⁺ 425.3

Reference Example 90
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [6- (3,3,4,4-tetrafluoropyrrolidin-1-yl) pyridin-3-yl] pyridazine- 4 (1H) -ON
A) 5-Nitro-2- (3,3,4,4-tetrafluoropyrrolidin-1-yl) pyridine
A mixture of cesium carbonate (100 g), tetrafluoropyrrolidine hydrochloride (10 g) and 2-chloro-5-nitropyridine (20 g) in DMF (200 ml) was stirred at room temperature for 90 hours, then water was added. And extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound as yellow crystals.
MS (ESI +): [M + H] ⁺ 266.1
B) 6- (3,3,4,4-Tetrafluoropyrrolidin-1-yl) pyridin-3-amine 5-nitro-2- (3,3,4,4-tetrafluoro in methanol (100 mL) A mixture of pyrrolidin-1-yl) pyridine (2.17 g) and 10% palladium carbon (533 mg) was stirred at room temperature for 3 hours under a hydrogen atmosphere, and then filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.88 g).
MS (API +): [M + H] ⁺ 236.2
C) 5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [6- (3,3,4,4-tetrafluoropyrrolidin-1-yl) pyridin-3-yl] Pyridazin-4 (1H) -one By the same method as in Step C of Reference Example 90, the title compound was obtained.
MS (API +): [M + H] ⁺ 487.1

Reference Example 91
5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] pyridazine-4 (1H )-on
A) 1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-amine
2,2,2-trifluoroethyl trifluoromethanesulfonate (1.54 g) was added dropwise to a suspension of 4-nitro-1H-pyrazole (500 mg) and potassium carbonate (1.22 g) in DMF (5 mL). The reaction mixture was stirred at room temperature for 4 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A suspension of the obtained residue and 10% palladium carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hours in a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (490 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.97 (2H, brs), 4.88 (2H, q, J = 9.1 Hz), 7.04 (1H, s), 7.10 (1H, s).
B) 5-Methoxy-3- (1-phenyl-1H-pyrazol-5-yl) -1- [1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] pyridazine-4 (1H) -one The title compound was obtained in the same manner as in Step C of Reference Example 89.
MS (API +): [M + H] ⁺ 417.4

Reference Example 92
1- [1- (Cyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (Cyclopropylmethyl) -1H-pyrazol-4-amine The title compound was obtained in the same manner as in Step A of Reference Example 91.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.24-0.33 (2H, m), 0.42-0.54 (2H, m), 1.02-1.20 (1H, m), 3.70-3.88 (4H, m), 6.87 (1H, s), 7.06 (1H, s).
B) 1- [1- (Cyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one Reference The title compound was obtained in the same manner as in Step 89 of Example 89.
MS (API +): [M + H] ⁺ 389.2

Reference Example 93
1- [1- (Dicyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (Dicyclopropylmethyl) -1H-pyrazol-4-amine
To a solution of 4-nitro-1H-pyrazole (500 mg), dicyclopropylmethanol (0.92 g) and triphenylphosphine (2.3 g) in THF (10 mL), diisopropyltoluene azodicarboxylate (1.9 M, 4.6 mL) was added. Added at room temperature. The reaction mixture was stirred at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A suspension of the obtained residue and 10% palladium carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hours in a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (140 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.11-0.24 (2H, m), 0.26-0.42 (4H, m), 0.47-0.63 (2H, m), 1.19-1.37 (2H, m), 2.80 (1H, t, J = 8.7 Hz), 3.73 (2H, s), 6.87 (1H, s), 7.08 (1H, s).
B) 1- [1- (Dicyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Step C of Reference Example 89.
MS (API +): [M + H] ⁺ 429.1

Reference Example 94
5-Methoxy-1- [1- (1-phenylethyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (1-Phenylethyl) -1H-pyrazol-4-amine The title compound was obtained in the same manner as in Step 91 of Reference Example 91.
B) 5-Methoxy-1- [1- (1-phenylethyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Step C of Reference Example 89.
MS (API +): [M + H] ⁺ 439.4

Reference Example 95
5-Methoxy-1- [1- (1-methylethyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (1-Methylethyl) -1H-pyrazol-4-amine The title compound was obtained in the same manner as in Step 91 of Reference Example 91.
B) 5-Methoxy-1- [1- (1-methylethyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Step C of Reference Example 89.
MS (API +): [M + H] ⁺ 377.0

Reference Example 96
1- [1- (1-Cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (1-Cyclopropylethyl) -1H-pyrazol-4-amine The title compound was obtained in the same manner as in Step A of Reference Example 93.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.39-0.50 (2H, m), 0.52-0.63 (1H, m), 0.65-0.76 (1H, m), 1.24-1.37 (1H, m), 1.60 (3H, d, J = 6.8 Hz), 3.56-3.70 (1H, m), 3.97 (2H, brs), 7.08 (1H, s), 7.28 (1H, s).
B) 1- [1- (1-Cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- On The title compound was obtained in the same manner as in Step C of Reference Example 89.
MS (API +): [M + H] ⁺ 403.1

Reference Example 97
5-Methoxy-1- [1- (2-methylpropyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one
A) 1- (2-Methylpropyl) -1H-pyrazol-4-amine The title compound was obtained in the same manner as in Step 91 of Reference Example 91.
MS (API +): [M + H] ⁺ 140.3
C) 5-Methoxy-1- [1- (2-methylpropyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The title compound was obtained in the same manner as in Steps A, B and C of Reference Example 89.
MS (API +): [M + H] ⁺ 391.1

Reference Example 98
1- [1- (Cyclobutylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one Reference Example 97 In the same manner as in Steps A to C of the above, the title compound (196 mg) was obtained.
MS (API +): [M + H] ⁺ 403.1

Reference Example 99
1- [1- (1-Cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one ( Small retention time)
Of 1- [1- (1-cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The racemate (140 mg) was fractionated by HPLC (column: CHIRALCEL OJ (MC001), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 100/900), and the one with the shorter retention time Of the title compound (63 mg).
MS (API +): [M + H] ⁺ 403.1

Reference Example 100
1- [1- (1-Cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one ( Large retention time)
Of 1- [1- (1-cyclopropylethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one The racemate (140 mg) was fractionated by HPLC (column: CHIRALCEL OJ (MC001), 50 mmID x 500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane / ethanol = 100/900), and the one with the longer retention time Of the title compound (63 mg).
MS (API +): [M + H] ⁺ 403.1

Reference Example 101
1- [1- (Cyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H)- on
A) 1-methoxy-3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) propan-2-one The title compound was obtained in the same manner as in Steps A and B of Reference Example 89.
MS (API +), found: 247.4
B) 1- [1- (Cyclopropylmethyl) -1H-pyrazol-4-yl] -5-methoxy-3- (3-methyl-1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H ) -One The title compound was obtained in the same manner as in Reference Example 92.
MS (API +), found: 403.4

Reference Example 102
5-Methoxy-1- {1-[(1-methylcyclopropyl) methyl] -1H-pyrazol-4-yl} -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -On The title compound was obtained in the same manner as in Reference Example 92.
MS (API +), found: 403.1

Reference Example 103
5-Methoxy-1- [1- (2,2,3,3,3-pentafluoropropyl) -1H-pyrazol-4-yl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -one The title compound was obtained in the same manner as in Reference Example 92.
MS (API +), found: 467.3

  The structural formulas of the compounds obtained in Reference Example 75-103 are shown in Tables 2-1 to 2-6 below.

Reference Example 104-121
The compound of Reference Example 104-121 was obtained in the same manner as in Reference Example 75-103. The structural formulas of the compounds are shown in Tables 3-1 to 3-4 below.

Reference Example 122
5- (Fluoromethoxy-d ₂ ) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON

1) Fluorioiodomethane-d ₂ :
Under an argon stream, diiodomethane-d ₂ (10 g) was placed in an oven-dried two-diameter round bottom flask equipped with a water cooling condenser in front of the solid addition system and the receiving flask. The ampoule was rinsed with Et ₂ O (2 ml) to complete the injection. HgF (6.8 g) was placed in the solid addition system and the system was evacuated to a residual pressure of 75 Torr while maintaining a slow flow of argon into the system. The flask containing diiodomethane-d ₂ was heated to 40 ° C. The receiving flask was placed in a dry ice alcohol bath, and the temperature in the reaction flask was raised to 65 ° C. To the stirred mixture, HgF was added portionwise over 105 minutes at 65-75 ° C. while maintaining the pressure in the system at 75 Torr. Heating was continued for 2 hours while gradually raising the temperature from 75 ° C to 100 ° C. The system was filled with argon and the contents in the receiving flask were distilled at atmospheric pressure to give the title compound (0.101 g) as a colorless liquid.

2) 5- (Fluoromethoxy-d ₂ ) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazol-5-yl) Pyridazine-4 (1H) -one:
1- {2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (51 mg) was weighed into a 10 ml oven dried round bottom flask. The flask was purged with argon. DMF (0.7 ml) was added and the resulting suspension was stirred briefly at 0 ° C. Under a stream of argon, 60% NaH (9 mg) in DMF was added to the mixture all at once. The mixture was stirred at 0 ° C. for 5 min, and a solution of fluoroiodomethane-d ₂ (20 mg) in DMF (0.2 ml) was added dropwise. The syringe and reagent vial were rinsed with DMF (0.5 ml) to complete the addition. The mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 2.5 hours. The ice-cold pale yellow solution was quenched with water (1 ml) and stirred for 5 minutes before partitioning between water (35 ml) and EtOAc (20 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 10 ml). The combined organic layers were washed with a mixture of brine (10 ml) and water (20 ml), then a mixture of brine (10 ml), water (10 ml) and 5% Na ₂ S ₂ O ₃ solution and finally The extract was washed with brine (15 ml), dried over MgSO ₄ , filtered through a cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / 1% Et ₃ N) to give the title compound (53 mg) as a white powder.
¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.66-1.82 (4H, m), 2.77 (1H, m), 3.40-3.61 (2H, m), 4.02-4.15 (2H, m), 6.37 (1H, t, J = 8.2 Hz), 6.87 (1H, d, J = 8.4 Hz), 7.03 (1H, m), 7.26-7.51 (6H, m), 7.79 (1H, d, J = 1.8 Hz), 8.13 ( (1H, d, J = 1.8 Hz).

Reference Example 123
5- (2-Fluoroethoxy-d ₄ ) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazol-5-yl) Pyridazine-4 (1H) -one

1) 2-Fluoroethyl-d ₄ -tosylate:
To a stirred solution of ethylene-d ₄ glycol (1.1 g) in CH ₂ Cl ₂ (20 ml) under a stream of argon, p-toluenesulfonyl chloride (7.3 g) and pyridine (8 g) in CH ₂ Cl ₂ (20 ml) The solution was added over 3 minutes. The mixture was stirred at room temperature for 18 hours. To the mixture was added CH ₂ Cl ₂ (20 ml) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water (40 ml) and extracted with CH ₂ Cl ₂ (10 + 5 ml). The combined organic layers were washed with 1 M HCl (40 ml), water (20 ml) and brine (40 ml), dried over Na ₂ SO ₄ , filtered through a cotton plug, and the filtrate was concentrated under reduced pressure. The crystalline solid was removed from the flask wall, crushed and dried under reduced pressure. To the resulting microcrystalline solid was added hot EtOAc (40 ml) and the mixture was heated until all material was dissolved. Hot hexane (10 ml) was added to the solution and the mixture was gently shaken and allowed to crystallize at room temperature for 2.5 days. The mixture was cooled at 4 ° C. for 2 hours and filtered. The crystals were washed with hexane (2 x 15 ml), EtOAc / hexane mixture (1/1, 15 ml), washed again with hexane (2 x 15 ml) to give ethylene-d ₄ ditosylate (4.9 g). White crystals were obtained.
To a stirred solution of ethylene-d ₄ ditosylate (0.52 g) in CH ₃ CN (16 ml) was added 1 M tetrabutylammonium fluoride in THF (1.8 ml) with a syringe under an argon atmosphere. The syringe was rinsed with CH ₃ CN (0.5 ml). The mixture was refluxed for 70 minutes and concentrated in vacuo. The residue was dissolved in EtOAc (30 ml) and washed with water (30 ml). The aqueous layer was extracted with EtOAc (10 ml). The combined organic layers were washed with brine (2 × 15 ml), dried over Na ₂ SO ₄ , filtered through a cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EtOAc / hexane) to give the title compound (0.12 g) as a colorless oil.

2) 5- (2-Fluoroethoxy-d ₄ ) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazole-5- Yl) pyridazine-4 (1H) -one:
1- {2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (50 mg) was weighed into a 4 ml glass vial and K ₂ CO ₃ (35 mg) was added. The vial was flushed with argon and DMF (0.6 ml) was added. To the stirred yellow suspension was added a solution of 2-fluoroethyl-d ₄ -tosylate (51 mg) in DMF (0.2 ml). The injection pipette and reagent vial were further rinsed with DMF (0.1 ml). The mixture was stirred for 20 hours at room temperature, 3 hours at 75 ° C., and 43 hours at room temperature. The mixture was treated with water and EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a mixture of saturated NaHCO ₃ (15 ml) and water (5 ml), then brine (20 ml), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with EtOAc / 1% Et ₃ N) to give a turbid solid. The turbid solid was dissolved in hot toluene (2 ml), and the resulting solution was concentrated under reduced pressure to obtain a foamy solid. The solid was triturated with Et ₂ O and hexane and the liquid was removed with a pipette. The residue was washed with hexane and dried under reduced pressure to give the title compound (51 mg) as an off-white fine powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.70-1.82 (4H, m), 2.77 (1H, m), 3.48-3.54 (2H, m), 4.07-4.11 (2H, m), 6.38 (1H, t, J = 8.4 Hz), 6.86 (1H, d, J = 8.4 Hz), 7.02 (1H, m), 7.26 (1H, m), 7.36-7.48 (5H, m), 7.77 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 2.0 Hz).

Reference Example 124
5- (Fluoromethoxy) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H )-on

1- {2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one To a stirred mixture of (70 mg) in DMF (2 mL) was added 60% sodium hydride (7.12 mg) at room temperature. The mixture was stirred at room temperature for 30 minutes and bromofluoromethane (27.4 mg) was added. The mixture was stirred at room temperature for 12 hours, treated with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / MeOH), and crystallized from EtOAc / hexane to give the title compound (40 mg) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.56-1.78 (4H, m), 2.78-2.94 (1H, m), 3.36-3.51 (2H, m), 3.87-4.01 (2H, m), 5.74 (1H, s), 5.92 (1H, s), 6.94 (1H, t, J = 8.3 Hz), 7.05 (1H, d, J = 1.5 Hz), 7.09-7.19 (1H, m), 7.29-7.49 (6H, m), 7.81 (1H, d, J = 1.9 Hz), 8.75 (1H, d, J = 1.9 Hz).
MS (API +): [M + H] + 465.2

Reference Example 125
5- (2-Fluoroethoxy) -1- {2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -ON

1- {2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl} -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one To a stirred mixture of (85 mg), 2-fluoroethanol (25.2 mg) and triphenylphosphine (103 mg) in THF (3 mL) was added 1.9 M diisopropyl azodicarboxylate (0.21 mL) in toluene at room temperature. It was. The mixture was stirred at room temperature for 1 hour, treated with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / hexane), and crystallized from EtOAc / IPE to give the title compound (40 mg) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.61-1.76 (4H, m), 2.80-2.95 (1H, m), 3.36-3.50 (2H, m), 3.88-4.01 (2H, m), 4.15-4.36 (2H, m), 4.59-4.84 (2H, m), 6.89-7.06 (2H, m), 7.14 (1H, dd, J = 8.3, 1.9 Hz), 7.28-7.48 (6H, m), 7.79 (1H, d, J = 1.9 Hz), 8.55 (1H, d, J = 2.3 Hz).
MS (API +): [M + H] + 479.2

Example Example 1
In ^[11 C] CH ₄ from ^[11 C] CH ₃ OTf producing protons 16.4 MeV of were obtained _{^{[11 C] CH 4 14 N}} (p, α) of nitrogen containing 10% hydrogen ¹¹ by C-reactive. Usually, the target gas was irradiated at a beam intensity of 35 μA for 10-20 minutes. The recirculation system was flushed with helium for 10-20 minutes before the release of radioactivity. [ ¹¹ C] CH ₃ I according to the published method (Applied Radiation and Isotopes, 1997. 48 (2): 153-157; Applied Radiation and Isotopes, 2009. 67 (1): 106-110.) Manufactured. That is, the released [ ¹¹ C] CH ₄ was passed through a phosphorus pentoxide trap (to remove traces of ammonia and water to be purified in the target) and collected in a HayeSep D trap cooled with liquid nitrogen. Nitrogen and hydrogen were removed by flowing helium. After collection, the micro diaphragm gas pump (NMP830KVDC, KNF Neuberger, Freiburg, Germany), 3 single oven, HayeSep D traps, as well as the recirculation system made of quartz, but containing iodine and ascarite, from the trap by heating ^[11 C] CH ₄ was released. First, [ ¹¹ C] CH ₄ was pumped into a quartz trough where it was mixed with vapor from iodine crystals at 60 ° C. and reacted at 720 ° C. After the reaction, [ ¹¹ C] CH ₃ I was collected in a HayeSep D trap at room temperature, and iodine and HI were trapped with ascarite while unreacted [ ¹¹ C] CH ₄ was recycled for 5 minutes. The HayeSep D trap was heated to 200 ° C. to release [ ¹¹ C] CH ₃ I. As previously described (Nucl Med Biol, 1995. 22 (2): 235-239), a soda glass column (inner diameter 3.7) containing [ ¹¹ C] CH ₃ I vapor and graphitized carbon impregnated with silver triflate. mm; length 150 mm; oven temperature 165 ° C.) to produce [ ¹¹ C] CH ₃ OTf. [ ¹¹ C] CH ₃ OTf was trapped at room temperature in a vessel containing the precursor to be labeled.

Example 2
1- [4- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5- [ ¹¹ C] methoxy) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -ON

(1) Methyl 2- (benzyloxy) acetate

A mixture of 2- (benzyloxy) acetic acid (20 g) and H ₂ SO ₄ (10 μL) in methanol (200 mL) was stirred at 70 ° C. for 2 hours and concentrated. The residue was treated with saturated NaHCO ₃ solution and extracted with AcOEt. The organic layer was dried over MgSO ₄ , passed through a silica gel pad and concentrated under reduced pressure to give the title compound (18.1 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 3.67 (3H, s), 4.17 (2H, s), 4.54 (2H, s), 7.16-7.54 (5H, m).

(2) 1- (Benzyloxy) pentane-2,4-dione

To a stirred mixture of methyl 2- (benzyloxy) acetate (17.6 g) and acetone (7.17 mL) in THF (20 mL) was added a suspension of sodium tert-butoxide (9.39 g) in THF (20 mL) at 0 ° C. It was dripped at. The mixture was stirred at 0 ° C. for 30 minutes and concentrated. The residue was treated with 1N HCl and extracted with AcOEt. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with AcOEt / hexane = 1/10) to give the title compound (11.3 g) as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 2.03-2.32 (3H, s), 4.09 (2H, s), 4.57 (2H, s), 5.86 (1H, s), 7.30-7.50 (5H, m) .

(3) 1- (Benzyloxy) -3-[(2-fluoro-4-iodophenyl) hydrazono] pentane-2,4-dione

To a stirred mixture of 2-fluoro-4-iodoaniline (5.75 g) and 6 N HClaq (24.3 mL), a solution of sodium nitrite (2.0 g) in water (6.1 mL) was added dropwise at 0 ° C. Stir at 20 ° C. for 20 minutes. The mixture was poured into a suspension of 1- (benzyloxy) pentane-2,4-dione (5 g) and sodium acetate (11.9 g) in MeOH (48 mL). The mixture was stirred at 0 ° C. for 20 minutes. Water (76 mL) was added to the mixture, and the precipitate was collected by filtration to give the title compound (10.7 g) as a yellow powder.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.39-2.53 (3H, m), 4.58 (2H, d, J = 6.4 Hz), 4.67 (1H, s), 4.80 (1H, s), 7.13 -7.47 (5H, m), 7.47-7.78 (2H, m), 7.78-8.00 (1H, m), 14.31 (1H, d, J = 5.3 Hz).

(4) 5- (Benzyloxy) -1- (2-fluoro-4-iodophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one

To a solution of 1- (benzyloxy) -3-[(2-fluoro-4-iodophenyl) hydrazono] pentane-2,4-dione (10.7 g) in DMA (30 mL), N, N-dimethylformamide dimethylacetal ( 9.38 mL) was added. The mixture was stirred at 80 ° C. for 2 hours and then concentrated. EtOH (200 mL) was added to the residue. To the stirred mixture was added phenylhydrazine (2.46 mL) and TFA (20 mL) in EtOH (180 mL) at 0 ° C. The mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with EtOH to give the title compound (8.95 g).
MS (API +): [M + H] + 565.3
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 5.08 (2H, s), 6.76 (1H, t, J = 8.3 Hz), 7.00 (1H, d, J = 1.9 Hz), 7.30-7.34 (2H , m), 7.35-7.43 (8H, m), 7.61 (1H, d, J = 8.3 Hz), 7.79 (1H, d, J = 1.9 Hz), 7.92 (1H, dd, J = 10.2, 1.5 Hz) , 8.60 (1H, d, J = 1.9 Hz).

(5) 5- (Benzyloxy) -1- [4- (3,3-difluoroazetidin-1-yl) -2-fluorophenyl] -3- (1-phenyl-1H-pyrazol-5-yl) Pyridazine-4 (1H) -one

5- (benzyloxy) -1- (2-fluoro-4-iodophenyl) -3- (1-phenyl-1H-pyrazol-5-yl) pyridazin-4 (1H) -one (564 mg) under argon atmosphere ), 3,3-difluoroazetidine hydrochloride (155 mg), Pd ₂ (dba) ₃ (220 mg), Xantphos (278 mg), and sodium tert-butoxide (250 mg) in 1,4-dioxane (5 mL) The suspension was stirred at room temperature for 48 hours. The reaction mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / AcOEt), and crystallized from hexane / AcOEt to give the title compound (145 mg) as an off-white powder.
MS (API +): [M + H] + 530.1
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 4.35 (4H, t, J = 12.5 Hz), 5.09 (2H, s), 6.35 (1H, dd, J = 8.5, 2.1 Hz), 6.60 (1H , dd, J = 12.8, 2.3 Hz), 6.79-6.99 (2H, m), 7.24-7.52 (10H, m), 7.78 (1H, d, J = 1.9 Hz), 8.49 (1H, d, J = 1.9 Hz).

(6) 1- [4- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H) -ON

Under H ₂ atmosphere, 5- (benzyloxy) -1- [4- (3,3-difluoroazetidin-1-yl) -2-fluorophenyl] -3- (1-phenyl-1H-pyrazole-5- A mixture of (yl) pyridazin-4 (1H) -one (135 mg) and 10% Pd-C (50 mg) in AcOEt (5 mL) and MeOH (5 mL) was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized from CH ₃ CN / H ₂ O. The obtained crystals were recrystallized from CH ₃ CN to give the title compound (70 mg) as a white powder.
MS (API +): [M + H] + 440.1
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 4.35 (4H, t, J = 12.3 Hz), 6.35 (1H, dd, J = 8.7, 1.9 Hz), 6.60 (1H, dd, J = 13.0, 2.5 Hz), 6.86-7.00 (2H, m), 7.24-7.47 (5H, m), 7.79 (1H, d, J = 1.9 Hz), 8.32 (1H, d, J = 2.3 Hz).

(7) 1- [4- (3,3-Difluoroazetidin-1-yl) -2-fluorophenyl] -5- [ ¹¹ C] methoxy) -3- (1-phenyl-1H-pyrazole-5- Yl) pyridazine-4 (1H) -one

Sodium hydroxide (0.5 M, 3-4 μL) was replaced with 1- [4- (3,3-difluoroazetidin-1-yl) -2-fluorophenyl] -5-hydroxy-3- (1-phenyl-1H After -pyrazol-5-yl) pyridazin-4 (1H) -one (0.2-0.5 mg) was added to a glass vial, acetone (500 μL) was added to the same vial and the mixture was mixed well. [ ¹¹ C] CH ₃ OTf (10-25 GBq) prepared in Example 1 was trapped in a vial at room temperature and incubated for 40-60 seconds. The reaction mixture was then diluted with the mobile phase used for HPLC purification. The diluted mixture was transferred to an Ascentis RP-Amide reverse phase HPLC column and eluted with a mixture of acetonitrile (MeCN) /0.1% aqueous triethylamine as the mobile phase. ^The fraction containing ¹¹ C-labeled compound was collected in a vial containing sterile water (50 ml) and sodium ascorbate (300 mg), and the labeled compound was adsorbed through a Waters Oasis HLB cartridge. The cartridge was then washed with distilled water (8 ml) and the ¹¹ C-labeled ligand was eluted with 99.6% ethanol (1.0 ml) into a vial containing sterile PBS (10 ml). Thereafter, the solution was filtered through a sterile 0.22 μm particle filter to obtain a sterile injection. Samples were taken from the final composition for radiochemical purity determination / pyrogenic testing.

Example 3
1- [2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -5- [ ¹¹ C] methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 ( 1H) -ON

(1) 4- (3,6-Dihydro-2H-pyran-4-yl) -2-fluoroaniline

2-Fluoro-4-iodoaniline (5.37 g), 2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( To a mixture of 5 g), palladium acetate (0.25 g) and X-phos (1.08 g) in DME (84 mL) was added a solution of cesium carbonate (18.5 g) in water (28 mL). Under an argon atmosphere, the mixture was stirred at 90 ° C. for 12 hours, diluted with water and extracted with AcOEt. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with hexane / AcOEt = 10/1 to 5/1) to give the title compound (3.2 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.29-2.40 (2H, m), 3.77 (2H, d, J = 11.0 Hz), 4.17 (2H, q, J = 2.9 Hz), 5.15 (2H , s), 6.05 (1H, dt, J = 3.0, 1.5 Hz), 6.72 (1H, dd, J = 9.5, 8.3 Hz), 6.99 (1H, dd, J = 8.3, 2.3 Hz), 7.08 (1H, dd, J = 13.4, 2.1 Hz).

(2) 2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) aniline

Mixture of 4- (3,6-dihydro-2H-pyran-4-yl) -2-fluoroaniline (3.62 g) and 10% Pd-C (0.36 g) in EtOH (75 mL) under H ₂ atmosphere The mixture was stirred at room temperature for 5 hours and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.53 g) as a white solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.46-1.70 (4H, m), 2.55-2.69 (1H, m), 3.33-3.47 (2H, m), 3.84-3.99 (2H, m), 4.88 (2H, brs), 6.61-6.80 (2H, m), 6.86 (1H, d, J = 12.8 Hz).

(3) 1- (Benzyloxy) -3-{[2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] hydrazono} pentane-2,4-dione

A solution of sodium nitrite (2.1 g) in water (10 mL) in a stirred suspension of 2-fluoro-4- (tetrahydro-2H-pyran-4-yl) aniline (4 g) in 6N HCl (20 mL) Was added under ice cooling. After the mixture was stirred at 0 ° C. for 2 hours, to a stirred mixture of 1- (benzyloxy) pentane-2,4-dione (4.23 g) and sodium acetate trihydrate (16.7 g) in MeOH (40 mL). Poured. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The precipitate was collected by filtration and washed with water and IPE to give the title compound (6.8 g).
MS (API +): [M + H] + 440.1
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.53-1.79 (4H, m), 2.31-2.42 (3H, m), 2.72-2.93 (1H, m), 3.37-3.57 (2H, m), 3.89 -3.99 (2H, m), 4.58 (2H, s), 4.71 (2H, brs), 7.02-7.47 (7H, m), 7.72 (1H, brs), 14.44 (1H, brs).

(4) 5- (Benzyloxy) -1- [2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine- 4 (1H) -ON

1- (Benzyloxy) -3-{[2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] hydrazono} pentane-2,4-dione (1.2 g) and N, N-dimethylformamide A mixture of dimethylacetal (1.2 mL) in DMF (15 mL) was stirred at 80 ° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in EtOH (15 mL) and TFA (1.5 mL) was added. Phenylhydrazine (0.33 g) was added to the stirred suspension at 0 ° C. The mixture was stirred at room temperature for 72 hours, treated with saturated NaHCO ₃ solution and extracted with AcOEt. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with AcOEt / hexane = 1/1 to 3/1) to give the title compound (0.8 g).
MS (API +): [M + H] + 523.1
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.59-1.76 (4H, m), 2.77-2.94 (1H, m), 3.36-3.51 (2H, m), 3.89-4.00 (2H, m), 5.09 (2H, s), 6.88-7.00 (2H, m), 7.14 (1H, d, J = 8.3 Hz), 7.29-7.51 (11H, m), 7.79 (1H, d, J = 1.9 Hz), 8.60 (1H, d, J = 2.3 Hz).

(5) 1- [2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -5-hydroxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H )-on

5- (Benzyloxy) -1- [2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -3- (1-phenyl-1H-pyrazol-5-yl) pyridazine-4 (1H A mixture of) -one (5.7 g) and 25% HBr in AcOH (40 mL) was stirred at 50 ° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with AcOEt. The organic layer was washed with a saturated NaHCO ₃ solution and an aqueous solution of Na ₂ S ₂ O ₃ (11.4 g), dried over MgSO ₄ and concentrated under reduced pressure. The residue was suspended in AcOEt (25 mL), and IPE (25 mL) was added. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and recrystallized from DMSO / EtOH to give the title compound (1.8 g).
MS (API +): [M + H] + 433.2
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.56-1.80 (4H, m), 2.76-2.94 (1H, m), 3.35-3.51 (3H, m), 3.88-4.02 (2H, m), 6.87-7.07 (2H, m), 7.11-7.15 (1H, m), 7.28-7.49 (6H, m), 7.79 (1H, d, J = 1.9 Hz), 8.41 (1H, d, J = 2.3 Hz) .

(6) 1- [2-Fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -5- [ ¹¹ C] methoxy-3- (1-phenyl-1H-pyrazol-5-yl) pyridazine -4 (1H) -ON

Sodium hydroxide (0.5 M, 3-4 μL) to 1- [2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl] -5-hydroxy-3- (1-phenyl-1H-pyrazole After adding to a glass vial containing -5-yl) pyridazin-4 (1H) -one (0.2-0.5 mg), acetone (500 μL) was added to the same vial and the mixture was mixed well. [ ¹¹ C] CH ₃ OTf (10-25 GBq) prepared in Example 1 was trapped in a vial at room temperature and incubated for 40-60 seconds. The reaction mixture was then diluted with the mobile phase used for HPLC purification. The diluted mixture was transferred to an Ascentis RP-Amide reverse phase HPLC column and eluted with a mixture of acetonitrile (MeCN) /0.1% aqueous triethylamine as the mobile phase. ^The fraction containing ¹¹ C-labeled compound was collected in a vial containing sterile water (50 ml) and sodium ascorbate (300 mg), and the labeled compound was adsorbed through a Waters Oasis HLB cartridge. The cartridge was then washed with distilled water (8 ml) and the ¹¹ C-labeled ligand was eluted with 99.6% ethanol (1.0 ml) into a vial containing sterile PBS (10 ml). Thereafter, the solution was filtered through a sterile 0.22 μm particle filter to obtain a sterile injection. Samples were taken from the final composition for radiochemical purity determination / pyrogenic testing.

Example 4-118
In the same manner as in Example 2-3, the compounds of Reference Examples 1-4 and 11-121 were radiolabeled with ¹¹ C.

Example 119
5-([ ¹⁸ F] fluoro-methyloxy-d ₂ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole- Synthesis of 5-yl) pyridazin-4 (1H) -one
(1) Production of bromo [ ¹⁸ F] fluoromethane from [ ¹⁸ F] fluoride
An [ ¹⁸ F] fluoride aqueous solution is prepared by ¹⁸ O (p, n) ¹⁸ F nuclear reaction, transferred from a cyclotron target by a helium stream (in a bolus of 1.5 mL [ ¹⁸ O] H ₂ O), and trapped by an ion exchange resin cartridge Then, [ ¹⁸ O] H ₂ O was distilled off. [ ¹⁸ F] fluoride was then eluted into the reaction vessel using 2 mL acetonitrile / water (96/4 v / v) containing 9.8 mg Kryptofix 2.2.2 and 1.8 mg potassium carbonate. The solvent was concentrated by heating to 140 ° C. under a nitrogen stream. A solution of 10-25 μL of deuterated dibromomethane dissolved in 1.0 ml of acetonitrile (MeCN) was added to the dried [ ¹⁸ F] fluoride / Kryptofix complex. The reaction mixture was heated in a sealed 10 ml conical reaction vial at 100 ° C. for 5 minutes without stirring. After the reaction, bromo [ ¹⁸ F] fluoromethane-d ₂ was cooled to −15 ° C. under a nitrogen stream, and the reaction mixture was distilled into a vial containing 250-350 μL of dimethylformamide (DMF).

(2) 5-([ ¹⁸ F] fluoro-methyloxy-d ₂ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H -Pyrazol-5-yl) pyridazine-4 (1H) -one

After adding 5-10 μL of 0.5 M NaOH aqueous solution to 0.75-1.50 mg of the compound obtained in Example 3 (5), the mixture was dissolved in approximately 300 μL of DMF, and the solution was dissolved in bromo [ ¹⁸ F] fluoro. Methane-d ₂ was added to the DMF solution. The resulting reaction mixture was heated at 130 ° C. for 10-15 minutes, cooled to room temperature, and diluted with the mobile phase used for HPLC purification. The diluted mixture was transferred to an Ascentis RP-Amide reverse phase HPLC column and eluted with a mixture of acetonitrile (MeCN) /0.1% aqueous triethylamine as the mobile phase. ^The fraction containing ¹⁸ F-labeled compound was collected in a vial containing 50 ml of sterile water and 300 mg of sodium ascorbate, and the labeled compound was adsorbed through a Waters Oasis HLB cartridge. The cartridge was then washed with 10 ml distilled water and the ¹⁸ F-labeled ligand was eluted with 1.0 ml 99.6% ethanol in a vial containing 10 ml sterile PBS. Thereafter, the solution was filtered through a sterile 0.22 μm particle filter to obtain a sterile injection. Samples were taken from the final composition for radiochemical purity determination / pyrogenic testing.

Example 120
5- (2- [ ¹⁸ F] fluoro-ethyloxy-d ₄ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole Synthesis of -5-yl) pyridazin-4 (1H) -one
(1) Production of 1-bromo-2- [ ¹⁸ F] fluoroethane-d ₄ from [ ¹⁸ F] fluoride
An [ ¹⁸ F] fluoride aqueous solution is prepared by ¹⁸ O (p, n) ¹⁸ F nuclear reaction, transferred from a cyclotron target by a helium stream (in a bolus of 1.5 mL [ ¹⁸ O] H ₂ O), and trapped by an ion exchange resin cartridge Then, [ ¹⁸ O] H ₂ O was distilled off. [ ¹⁸ F] fluoride was then eluted into the reaction vessel using 2 mL acetonitrile / water (96/4 v / v) containing 9.8 mg Kryptofix 2.2.2 and 1.8 mg potassium carbonate. The solvent was concentrated by heating to 140 ° C. under a nitrogen stream. 10-25 μL of deuterated 1-tosyl-2-bromoethane dissolved in 0.7 ml of dichlorobenzene (o-DCB) was added to the dried [ ¹⁸ F] fluoride / Kryptofix complex. The reaction mixture was heated in a sealed 10 ml conical reaction vial at 135 ° C. for 5 minutes without stirring. After the reaction, 1-bromo-2- [ ¹⁸ F] fluoroethane-d ₄ is cooled to −15 ° C. in a nitrogen stream, and the reaction mixture is poured into a vial containing 250-350 μL of dimethylformamide (DMF). Distilled on.

(2) 5- (2- [ ¹⁸ F] fluoro-ethyloxy-d ₄ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl- 1H-pyrazol-5-yl) pyridazin-4 (1H) -one

After adding 5-10 μL of 0.5 M NaOH aqueous solution to 0.75-1.50 mg of the compound obtained in Example 3 (5), the mixture was dissolved in approximately 300 μL of DMF, and the solution was dissolved in 1-bromo-2- [ ¹⁸ F] fluoroethane-d ₄ was added to the DMF solution. The resulting reaction mixture was heated at 130 ° C. for 10-15 minutes, cooled to room temperature, and diluted with the mobile phase used for HPLC purification. The diluted mixture was transferred to an Ascentis RP-Amide reverse phase HPLC column and eluted with a mixture of acetonitrile (MeCN) /0.1% aqueous triethylamine as the mobile phase. ^The fraction containing ¹⁸ F-labeled compound was collected in a vial containing 50 ml of sterile water and 300 mg of sodium ascorbate, and the labeled compound was adsorbed through a Waters Oasis HLB cartridge. The cartridge was then washed with 10 ml distilled water and the ¹⁸ F-labeled ligand was eluted with 1.0 ml 99.6% ethanol in a vial containing 10 ml sterile PBS. Thereafter, the solution was filtered through a sterile 0.22 μm particle filter to obtain a sterile injection. Samples were taken from the final composition for radiochemical purity determination / pyrogenic testing.

Test example Test example 1
PET measurement ([ ¹¹ C] compound)
Two rhesus monkeys weighing 4450 g and 5000 g were used, and PET measurement was performed with a high-resolution research tomography apparatus (HRRT) (Siemens Molecular Imaging). During PET measurements, monkeys were maintained under sevoflurane, oxygen, and medical air gas anesthesia. Dynamic brain PET data collected in wrist mode for 123 minutes after intravenous injection of 150 and 162 M Bq of [ ¹¹ C] compound of Example 2 and 159 and 162 M Bq of Example 3 [ ¹¹ C] compound did. List-mode data was reconstructed using the ordinary Poisson-3D-ordered subset expectation maximization (OP-3D-OSEM) algorithm with 10 iterations and 16 subsets including point spread function (PSF) modeling . During PET data collection, venous blood was sampled for metabolic analysis. The results are shown in FIG. 1 and FIG.
FIG. 1 shows the parent fraction of the radioligand of Example 2.
FIG. 2 shows the parent fraction of the radioligand of Example 3.
The fraction of the parent compound of Example 2 was 70-76% in 30 minutes and 52-58% in 90 minutes.
The fraction of the parent compound of Example 3 was 56-57% in 30 minutes and 45-53% in 90 minutes.

PET measurement ([ ¹⁸ F] compound)
Three cynomolgus monkeys weighing between 3730 g and 4845 g were used, and PET measurement was performed using a high-resolution research tomography system (HRRT) (Siemens Molecular Imaging). During PET measurements, monkeys were maintained under sevoflurane, oxygen, and medical air gas anesthesia. 148 and 157 after ^[18 F] compounds of M Bq of Example 119 and Example 120 of 159 and 163 M Bq of ^[18 F] compounds injected intravenously, collect dynamic brain PET data 180 min list mode did. List-mode data was reconstructed using the ordinary Poisson-3D-ordered subset expectation maximization (OP-3D-OSEM) algorithm with 10 iterations and 16 subsets including point spread function (PSF) modeling . During PET data collection, venous blood was sampled for metabolic analysis. The results are shown in FIG. 11 and FIG.
FIG. 11 shows the parent fraction of the radioligand of Example 119.
FIG. 12 shows the parent fraction of the radioligand of Example 120.
The fraction of the parent compound of Example 119 was 62-71% in 60 minutes and 60-63% in 180 minutes.
The fraction of the parent compound of Example 120 was 64-74% at 60 minutes and 51-72% at 180 minutes.

Test example 2
MRI measurement
T1-weighted MR images were obtained using the MRI system GE 1.5 T Signa unit (Milwaukee, WI, USA). The T1 sequence was a 3-D SPGR protocol with the following settings: repetition time (TR) 21 ms, flip angle 35 °, FOV 12.8, matrix 256 × 256 × 128, 128 × 1.0 mm slice.

Test example 3
Data analysis ([ ¹¹ C] compound)
Regions of interest (ROIs) for caudate nucleus, putamen, nucleus accumbens, thalamus, cerebellum, frontal lobe, temporal lobe and whole brain using PMOD software (v3.1 PMOD Technologies Ltd. Zurich, Switzerland) Drawn on MRI / PET co-recorded image. Time activity curves were generated for these regions. % ID (= total radioactivity in the brain (MBq) x 100 / injected radioactivity (MBq)) or% SUV (= radioactivity in the region (MBq / cc) x 100 / (injected radioactivity ( MBq) / weight (g))). Metabolic fractions in plasma were measured by radioactive LC analysis. The results are shown in FIGS. 3, 4, 5, 6, 7, 8, 9 and 10.
FIG. 3 shows whole brain uptake of Examples 2 and 3 (% ID, 2 rhesus monkeys).
FIG. 4 shows the whole brain uptake of Examples 2 and 3 (% SUV, 2 rhesus monkeys).
FIG. 5 shows the local brain uptake of Example 2 (% SUV).
FIG. 6 shows the local brain uptake of Example 3 (% SUV).
FIG. 7 shows the time course of specific radioligand binding of Example 2.
FIG. 8 shows the time course of specific radioligand binding of Example 3.
FIG. 9 shows the change with time of the ratio of the target area to the reference area (Example 2).
FIG. 10 shows the change over time in the ratio of the target area to the reference area (Example 3).

  The uptake of Example 2 in the whole brain peaked at 2.5-7.5 minutes. The peak uptake was 3.3-5.1% ID. Thereafter, uptake decreased by half in 60-66 minutes. The local brain uptake of Example 2 peaked in all regions during the PET measurement. The putamen showed the highest uptake, followed by the caudate nucleus, the nucleus accumbens and the thalamus. Uptake was lowest in the cerebellum, frontal lobe, and temporal lobe. The specific binding of Example 2 in the putamen, which subtracted the uptake in the putamen from the uptake in the putamen, had a peak at 48 minutes. The ratio of specific binding between target area uptake and cerebellar uptake in Example 2 increased to approximately 2.5-2.7 between 123 min PET measurements.

  The uptake of Example 3 in the whole brain peaked at 2 minutes. The peak uptake was 3.3-4.1% ID. Since then, the washout of uptake has been abrupt, and uptake has been halved in 30 minutes. The local brain uptake of Example 3 peaked in all regions during the PET measurement. The putamen showed the highest uptake, followed by the caudate nucleus, the nucleus accumbens and the thalamus. Uptake was lowest in the cerebellum, frontal lobe, and temporal lobe. The specific binding of Example 3 in the putamen, subtracting the cerebellar uptake from the putamen uptake, had a peak at 42 minutes. The ratio of specific binding between uptake in the target area and uptake in the cerebellum in Example 3 increased to approximately 6 between 123 minutes of PET measurement.

Data analysis ([ ¹⁸ F] compounds)
Regions of interest (ROIs) for caudate nucleus, putamen, nucleus accumbens, thalamus, cerebellum, frontal lobe, temporal lobe and whole brain using PMOD software (v3.2 PMOD Technologies Ltd. Zurich, Switzerland) Drawn on MRI / PET co-recorded image. Time activity curves were generated for these regions. % ID (= total radioactivity in the brain (MBq) x 100 / injected radioactivity (MBq)) or% SUV (= radioactivity in the region (MBq / cc) x 100 / (injected radioactivity ( MBq) / weight (g))). Metabolic fractions in plasma were measured by radioactive LC analysis. The results are shown in FIGS. 13, 14, 15, 16, 17, 18, 19 and 20.
FIG. 13 shows whole brain uptake of Examples 119 and 120 (% ID, 3 cynomolgus monkeys).
FIG. 14 shows whole brain uptake of Examples 119 and 120 (% SUV, 3 cynomolgus monkeys).
FIG. 15 shows the regional brain uptake of Example 119 (% SUV).
FIG. 16 shows the local brain uptake of Example 120 (% SUV).
FIG. 17 shows the time course of specific radioligand binding of Example 119.
FIG. 18 shows the time course of specific radioligand binding of Example 120.
FIG. 19 shows the change with time of the ratio of the target area to the reference area (Example 119).
FIG. 20 shows the change with time of the ratio of the target area to the reference area (Example 120).

  The uptake of Example 119 in the whole brain peaked at 2.5 minutes. The peak uptake was 5.2-5.7% ID. Thereafter, uptake decreased by half in 23 minutes. For local brain uptake of Example 119, peaks were reached in all regions during the PET measurement. The putamen showed the highest uptake, followed by the caudate nucleus, the nucleus accumbens and the thalamus. Uptake was lowest in the cerebellum, frontal lobe, and temporal lobe. The specific binding of Example 119 in the putamen, subtracting the cerebellar uptake from the putamen uptake, had a peak at 18.5-29 min. The ratio of specific binding between uptake at the target area and uptake at the cerebellum in Example 119 increased to approximately 3.0-3.9 between 47-65 min PET measurements.

  The uptake of Example 120 in the whole brain peaked at 2.5-4.5 minutes. The peak uptake was 3.6% ID. Subsequently, uptake decreased in half in 23-35 minutes. For regional brain uptake of Example 120, peaks were reached in all regions during the PET measurement. The putamen showed the highest uptake, followed by the caudate nucleus, the nucleus accumbens and the thalamus. Uptake was lowest in the cerebellum, frontal lobe, and temporal lobe. Specific binding of Example 120 in the putamen, subtracting the cerebellar uptake from the putamen uptake, had a peak at 35-41 min. The ratio of specific binding between uptake at the target area and uptake at the cerebellum in Example 120 increased to approximately 1.5-1.9 between 65-75 min PET measurements.

Test example 4
PDE10A enzyme inhibition Human PDE10A enzyme was produced from Sf9 or COS-7 cells into which the full-length gene was introduced. Cloned enzyme was extracted from the homogenized cell pellet. The extracted enzyme from Sf9 cells was partially purified using a His-tag affinity column. The enzyme was stored at -70 ° C until used. PDE activity was measured using SPA (Scintillation Proximity Assay) (GE Healthcare). To assess inhibitory activity, 10 μL of serially diluted compounds are combined with 20 μL of PDE enzyme in assay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl ₂ , 1.7 mM EGTA, 0.1% BSA (pH 7.4)). And incubated at room temperature for 30 minutes. Compounds were measured in duplicate in 96 well half area plates (Corning) and the final concentration of DMSO in the assay system was 1 percent. Add 10 μL of substrate [ ³ H] cGMP (25 or 50 nM; shipped with GE Healthcare SPA kit or purchased from PerkinElmer, respectively) to add a final assay volume of 40 μL Started. After incubation at room temperature for 60 minutes, yttrium SPA beads containing zinc sulfate were added (20 μL, 6 mg / mL) to stop the PDE enzymatic reaction. After leaving still for 60 minutes, the assay plate was measured with a scintillation counter (Perkin Elmer), and the inhibition rate was calculated. IC ₅₀ values were calculated based on 0% control wells with DMSO and 100% control wells without enzyme. The results are shown in Table 4.

Test Example 5
PDE family enzyme inhibition (selectivity assay)
Human PDE1A, 3A, 4D2, 5A1, 7B, 8A1, 9A2, and 11A4 enzymes were purchased from BPS Biosciences. Human PDE6AB enzyme was purchased from Scottish Biomedical. PDE2A3 enzyme was produced from Sf9 into which the full-length gene was introduced. PDE activity was measured using SPA (Scintillation Proximity Assay) (GE Healthcare). To assess inhibitory activity, 10 μL of serially diluted compounds are combined with 20 μL of PDE enzyme in assay buffer (50 mM HEPES-NaOH, 8.3 mM MgCl ₂ , 1.7 mM EGTA, 0.1% BSA (pH 7.4)). And incubated at room temperature for 30 minutes. Compounds were measured in duplicate in 96 well half area plates (Corning) and the final concentration of DMSO in the assay system was 1 percent. 10 μL of substrate [ ³ H] cGMP (PerkinElmer) for PDE1A, 2A3, 5A1, 6AB, 9A2, and 11A4 or 10 μL of substrate [ ³ H] cAMP (PerkinElmer) for PDE3A, 4D2, 7B, and 8A1 The reaction was started by adding a final assay volume of 40 μL. After incubation at room temperature for 60 minutes, yttrium SPA beads containing zinc sulfate were added (20 μL, 6 mg / mL) to stop the PDE enzymatic reaction. After leaving still for 60 minutes, the assay plate was measured with a scintillation counter (Perkin Elmer), and the inhibition rate was calculated. IC ₅₀ values were calculated based on 0% control wells with DMSO and 100% control wells without enzyme. Selectivity was defined as the ratio of the IC ₅₀ of each PDE other than PDE10A to the IC ₅₀ of PDE10A. The results are shown in Table 4.

The radiolabeled compounds of the present invention are useful as radiotracers for quantitative imaging of PDE10A in mammals.
This application is based on patent application numbers 1150757-1 and 1250925-3 filed in Sweden, the contents of which are fully incorporated herein.

Claims (13)

Formula (I ′):
[Wherein ring A ′ is
(1) benzene, optionally substituted with 1 to 4 substituents selected from (1) a halogen atom, and (2) a C _1-4 alkoxy group,
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B is a halogen atom, a hydroxy group, a cyano group, an oxo group, a C _1-10 alkoxy-carbonyl group, a C _1-10 alkoxy group optionally substituted with halogen, and a C optionally substituted with halogen. Optionally substituted with 1 to 4 substituents selected from _1-10 alkyl groups,
(1) C _3-12 cycloalkyl,
(2) dihydropyranyl,
(3) tetrahydropyranyl,
(4) azetidinyl,
(5) pyrrolidinyl,
(6) piperidinyl,
(7) imidazolyl,
(8) isoxazolyl,
(9) pyrazolyl,
(10) dihydropyrazolyl,
(11) pyridyl,
(12) pyrrolyl,
(13) dihydropyrrolyl,
(14) phenyl,
(15) morpholinyl,
(16) thiazolyl,
(17) oxazolidinyl,
(18) imidazolidinyl,
(19) selected from the group consisting of oxaazabicyclooctyl and (20) oxazepanyl (however, an optionally substituted formula
(In the formula, p is 1 to 4) .
R ¹ is, C _1-4 alkoxy group, a halogen atom and C _3-7 1 or more may be substituted with a substituent C _1-4 alkoxy group selected from cycloalkyl groups are the substituted _Optional C _1-4 alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an optionally substituted C _1-10 alkyl group or an _optionally substituted C _6-14 aryl group;
R ³ is a halogen atom, an optionally substituted C _1-10 alkyl group or an optionally substituted C _1-10 alkoxy group;
m is 0 or 1; and n is 0-3. ]
Represented by the formula (however,
1- [4- (3,5-dimethyl-isoxazol-4-yl) -2-fluorophenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine-4 ( 1H) -On and
1- (2-fluoro-4- (morpholin-4-yl) phenyl) ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) - pyridazine -4 (IH) - On except for)
Or a salt thereof. Ring A ′ is
(I) (1) a halogen atom, and (2) benzene substituted with 1 to 4 substituents selected from C _1-4 alkoxy groups,
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B may be substituted with 1 to 4 substituents selected from a halogen atom and an oxo group,
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ is a C _1-4 alkoxy group which may be substituted with one or more substituents selected from a halogen atom, a C _1-4 alkoxy group and a C _3-7 cycloalkyl group, and the C _{1 -4} alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom, a C _1-10 alkyl group, or a C _1-10 alkoxy group;
m is 0 to 1; and n is 0 or 1.
The compound according to claim 1 or a salt thereof. Ring A ′ is
(I) (1) a halogen atom, and (2) benzene substituted with 1 to 4 substituents selected from C _1-4 alkoxy groups,
(Ii) piperidine, or (iii) tetrahydropyridine;
Ring B may be substituted with 1 to 4 substituents selected from a halogen atom and an oxo group,
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ is ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O—;
R ² is a halogen atom, an alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom, a C _1-10 alkyl group, or a C _1-10 alkoxy group;
m is 0 to 1; and n is 0 or 1.
The compound according to claim 1 or a salt thereof. Ring A ′ is
(I) benzene substituted with 1 to 4 halogen atoms;
Ring B may be substituted with 1 to 4 halogen atoms,
Selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl;
R ¹ is a C _1-4 alkoxy group which may be substituted with one or more substituents selected from a halogen atom, a C _1-4 alkoxy group and a C _3-7 cycloalkyl group, and the C _{1 -4} alkoxy is radiolabeled with ¹¹ C or ¹⁸ F;
R ² is a halogen atom, an alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom, a C _1-10 alkyl group, or a C _1-10 alkoxy group;
m is 0 to 1; and n is 0 or 1.
The compound according to claim 1 or a salt thereof. Ring A ′ is
(I) benzene substituted with 1 to 4 halogen atoms;
Ring B is selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl, optionally substituted with 1 to 4 halogen atoms;
R ¹ is ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O—;
R ² is a halogen atom, an alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom, a C _1-10 alkyl group, or a C _1-10 alkoxy group;
m is 0 to 1; and n is 0 or 1.
The compound according to claim 1 or a salt thereof. Ring A ′ is
(I) benzene substituted with 1 to 4 halogen atoms;
Ring B is selected from the group consisting of (1) tetrahydropyranyl, and (2) azetidinyl, optionally substituted with 1 to 4 halogen atoms;
R ¹ is ¹¹ CH ₃ O—, ¹⁸ FCH ₂ O—, ¹⁸ FCD ₂ O—, ¹⁸ FCH ₂ CH ₂ O— or ¹⁸ FCD ₂ CD ₂ O—;
R ² is a halogen atom, an alkyl group _optionally substituted with halogen, or a C _6-14 aryl group;
R ³ is a halogen atom, a C _1-10 alkyl group, or a C _1-10 alkoxy group;
m is 0 to 1; and n is 0 or 1.
The compound according to claim 1 or a salt thereof.   The compound or a salt thereof according to claim 1, wherein both m and n are 0. 1- [2-fluoro-4- (tetrahydro -2H- pyran-4-yl) phenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine -4 (IH ) -One or a salt thereof. 1- [4- (3,3-difluoro-1-yl) -2-fluorophenyl] ^-5-11 C-methoxy-3- (1-phenyl -1H- pyrazol-5-yl) pyridazine -4 (1H) -one or a salt thereof. 5-([ ¹⁸ F] fluoro-methyloxy-d ₂ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole- 5-yl) pyridazin-4 (1H) -one or a salt thereof. 5- (2- [ ¹⁸ F] fluoro-ethyloxy-d ₄ ) -1- (2-fluoro-4- (tetrahydro-2H-pyran-4-yl) phenyl) -3- (1-phenyl-1H-pyrazole -5-yl) pyridazin-4 (1H) -one or a salt thereof.   A sterile composition comprising the compound of claim 1 or a salt thereof dissolved in physiological saline.   The compound of claim 1 or a salt thereof for use for quantitative imaging of PDE10A.